We help companies find early stage life science technologies from universities worth licensing — and map the fastest and cost effective path to develop them.
Summary: The NCI seeks research co-development partners and/or licensees for the sulfatide analog, C24:2 Description of Technology: Lung metastases represent a major clinical challenge in advanced cancer, with poor survival rates and no effective therapies to prevent their development. Researchers at the National Cancer Institute (NCI) have developed C24:2, a first-in-class synthetic 3-O-sulfo-galactosylceramide analog. After lysosomal processing by dendritic cells, C24:2 switches immune specificity to activate type I NKT cells, triggering a potent IFN-γ–mediated Th1 response. This novel mechanism significantly reduces lung metastases in preclinical models and positions C24:2 as a promising candidate for next-generation cancer immunotherapy. The structure and synthesis procedure of C24:2 are described in Patent Cooperation Treaty PCT/US2019/023890 which corresponds to E-100-2018 and for which Dr. Jay Berzofsky is the lead inventor. ....
Degeneration of retinal tissues occurs in many ocular disorders resulting in the loss of vision. Dysfunction and/or loss of Retinal Pigment Epithelium Cells (RPE) and disruption of the associated blood retinal barrier (BRB) tissue structures are linked with many ocular diseases and conditions including: age-related macular degeneration (AMD), Best disease, and retinitis pigmentosa. Engineered tissue structures that are able to replicate the function of lost BRB structures may restore lost vision and provide insight into new treatments and mechanisms of the underlying conditions. Scientists at the National Eye Institute (NEI) have developed a technology for a 3D bioprinting process. Through the process, an artificial blood retinal barrier (BRB) is constructed that may be used as a graft to potentially replace BRB tissues that are lost or damaged in many ocular disorders. The layers of BRB structures are printed as “bio-ink” (a...
This invention identifies a monoclonal antibody (4G10) against the chemokine receptor CXCR4 and is a mouse IgG1 antibody. CXCR4 has been identified as a co-receptor mediating entry of HIV-1 into T cells. Subsequently, CXCR4 has been implicated in normal physiological functions, including activation of B cells and B cell progenitors and guiding their migration into the bone marrow (via its ligand SDF-1). CXCR4 also functions in T cell progenitor migration and neural progenitor stem cell activation. Since 4G10 is a monoclonal antibody raised against a synthetic peptide derived from the N- terminus of CXCR4 that may prove useful in the context of the above CXCR4 functions, 4G10 is an excellent reagent for detection and quantitation of CXCR4 by Western blot, immunoprecipitation, ELISA, and flow cytometry. It can also be used to purify CXCR4 by affinity chromatography. With these known characteristics, it would also function in...
This CDC developed collection device is a small (approximately 1 cubic foot) open-sided container that attracts mosquitoes seeking a daytime resting location. The container is dark-colored and constructed of molded wood-fiber or recycled, high-density plastic. Mosquitoes that enter the dark space of the container are aspirated through a battery-powered fan into a collection receptacle. The receptacle is especially attractive to Culex and Anopheles mosquitos' vectors of West Nile Virus and malaria parasites, respectively. For research aims, this device avoids the sampling biases associated with CO 2 -baited traps (attracting mosquitoes in host-seeking mode, about a tenth of the population, and only females) or ovitraps/gravid traps (attract egg-laying females, again about a tenth of the population), making this device superior to other mosquito-sampling traps currently in use. Because all adult mosquitoes must find secluded locations...
A biofluid biomarker to reliably diagnose Cerebral Amyloid Angiopathy (CAA) and predict the risk of Amyloid-Related Imaging Abnormalities (ARIA) in Alzheimer’s disease patients.
Norovirus is a leading cause of vomiting, diarrhea, and foodborne illness worldwide, with 700 million cases and 200,000 deaths occurring each year. Despite decades of work in the field, there are no preventive or therapeutic strategies specifically approved for even the most prevalent forms of human norovirus (i.e., GI, GII genogroups), which are highly contagious and carry an increased risk of severe complications in children, older adults, and those with immunocompromising conditions. Researchers at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID) have isolated the first broadly reactive monoclonal antibody against GI genogroup noroviruses (mAbs16E10) using samples from a human blood donor. Results of in vitro and in vivo analyses further supported the antibody’s broad binding and blocking specificity to the entire GI norovirus genogroup, neutralization of the GI.1 type, and abrogation...
CDC scientists have developed a device for simultaneous rapid diagnosis of HIV infection and for identification of recent HIV-1 infection. The device utilizes immunochromatographic or flow-through principles to detect HIV antibodies within clinical samples. This device may be used for diagnosis of HIV infection, as well as to distinguish between recent infection ( 1 year). This latter application has added significance for surveillance, counseling, partner notification and other related prevention concerns, including the estimation of HIV incidence in cross-sectional populations. The device, if formatted as a self-contained kit, would utilize a single platform containing all required reagents, making it simple and easy for use by minimally trained technicians. The entire testing process, including the determination of incident infections, has been designed to minimize assay processing time. This device has potential as an important...
BSR T7/5 cells represent a foundational advancement in virology, offering a robust platform for the recovery of RNA viruses via reverse genetics. Established over 20 years ago, these cells have proven instrumental in the recovery of a wide array of RNA viruses, particularly those belonging to the mononegavirales order. By enabling the insertion of antigenome sequences into cDNA plasmids under a T7 RNA polymerase promoter, BSR T7/5 cells facilitate the transcription of RNA antigenomes and mRNA encoding RNP elements, leading to the assembly of infectious viruses. Notably, this system does not require helper viruses, and the cell line's permissiveness, attributed to the absence of a functional type 1 interferon response, makes it especially valuable for viruses replicating in the cytoplasm. Commercial applications: The applications of BSR T7/5 cells extend across various fields, offering immense potential in virology, vaccine...
Mutations in the p53 gene are associated with 50% of all cancers and nearly 80% of the p53 mutations are missense changes. We have developed genetic assays based in yeast that can functionally categorize expressed p53 mutant proteins. The combined assays are referred to as the FIP53 system. Because human p53 cDNA can be conveniently cloned in yeast, the FIP53 system provides a rapid and sophisticated system for the functional analysis of p53 mutants. Four categories of mutations have already been identified. The FIP53 system provides the first in vivo battery for tests that can subdivide many p53 mutations that can occur in humans. In particular, the FIP53 system may allow the identification of rare or new alleles that may function better than the wild type. Commercial applications: The FIP53 system provides a convenient genetic system for categorizing human mutations. It can also be used to assay potential drug impacts on p53 and for...
This invention includes HeLa cells that are engineered to inducibly express a mutant form of ornithine decarboxylase that is targeted to the mitochondrial matrix and forms insoluble protein aggregates. The presence of unfolded proteins in the matrix causes the accumulation of the mitochondrial kinase PINK1 and the E3 ubiquitin ligase PARK2/Parkin. These proteins play a critical role in degrading the mitochondria where they are expressed, a process call mitophagy. Mutations in these two genes are associated with familial Parkinson disease. Commercial applications: This cell line provides a unique and physiologically-relevant method to assess compounds that increase PINK1 activity. Competitive advantages: Prior models of PINK1/Parkin activation relied on mitochondrial depolarizing agents. This model may be more physiological and subtle, allowing a more valid way to assess compounds that increase PINK1 activity. Source institute: NINDS....
This technology includes in vitro-generated trophectoderm (TE) cells, which are ideal for modeling diseases of the placenta, drug screening, and cell-based therapies. The TE lineage which gives rise to placental cells during early human development. Derivation of definitive placental cells from human pluripotent stem cells in culture remains controversial and so far, placental cells can only be derived directly from primary placental tissue, which largely limits their access and study in the laboratory. This invention describes highly efficient TE differentiation, including cytotrophoblast and syncytiotrophoblast cells, by manipulating specific cell signaling pathways in chemically defined conditions. Commercial applications: This invention will significantly improve the use of human astrocytes for basic research, drug discovery, disease modeling, and cell therapy. Competitive advantages: This is the most efficient and most...
Description of Technology: Biofilms are complex microbial communities, surface attached and held together by self-produced polymer matrices. These matrices are mainly composed of polysaccharides, secreted proteins and nucleic acids. Poly-N-acetyl glucosamine (PNAG) is a highly conserved surface polysaccharide expressed by a range of bacterial, fungal and protozoan microorganisms. It is associated with microbial biofilm formation. Partial deacetylation of PNAG (dPNAG) is critical for the function of PNAG in biofilm formation and required for the structural development and integrity of biofilm. Antibodies to PNAG and/or dPNAG have significant potential as broad-spectrum therapeutics for a range of bacterial and fungal infections. Research suggests that dPNAG is a better target than PNAG for antibody-based therapeutics; however, identification of dPNAG antibodies has been challenging. Researchers at the National Cancer Institute (NCI)...
The HEK293T/T7 cell line is a novel development in virology research, particularly for studying human noroviruses. This cell line expresses the T7 RNA polymerase, a key enzyme used in reverse genetics systems. Unlike existing technologies, the HEK293T/T7 cell line offers the unique advantage of being able to produce functional T7 RNA polymerase, which is essential for driving transcription from T7 promoters. This capability opens up new possibilities for studying human noroviruses, which cannot be propagated in cell culture, and may facilitate the development of a reverse genetics system for these viruses. Overall, the HEK293T/T7 cell line represents a significant advancement in virology research and offers a valuable tool for researchers studying virus-host interactions and developing therapeutics or vaccines. Commercial applications: The HEK293T/T7 cell line has a wide range of potential applications in virology research and beyond....
Discovery and use of retina-specific promoters to rescue photoreceptor function specifically at clinically relevant, advanced stages of disease. Problem: Despite the fact that retinal gene therapy studies have shown promising results in animal models, treatment of advanced retinal degeneration with currently available gene therapies have not been successful. Because patients are usually diagnosed with progressive retinal degeneration at advanced stages of disease, structural and cellular remodeling of the retina found at later stages of disease affect the ability for genetic therapies to promote regeneration and rescue of the photoreceptors in the retina. Solution: The authors have identified retina-specific promoters that drive gene expression in advanced stages of retinal degeneration. These promoters can upregulate specific genes in degenerated retinae with low viral titers, high efficacy, and higher cell-specificity than the...
This technology is directed to the discovery of specific microRNAs that target and downregulate enzymes within the cholesterol biosynthetic pathway and is currently being tested in vivo. Briefly, microRNAs regulate the translation of messenger RNAs (mRNAs) into protein. The inventors have discovered a set of specific microRNAs that downregulate the expression of multiple enzymes in the cholesterol biosynthetic pathway. Importantly, this technology may provide the benefits of cholesterol lowering therapies to patients that are not suited for statin-based treatments. Statins block the cholesterol biosynthetic pathway at a single enzymatic step and may result in the deleterious build-up of a metabolic intermediate. In contrast, this technology simultaneously targets the expression of multiple enzymes required for cholesterol biosynthesis and thus may avoid the build-up of metabolic intermediates. The reduction of cholesterol biosynthesis...
The transfusion of regulatory T cells (Tregs) has been used in the clinic to successfully prevent graft vs. host disease and is currently being evaluated in the treatment of other autoimmune diseases, such as organ graft rejection, type 1 diabetes and multiple sclerosis. Prior to transfusion, adoptive regulatory T cell transfer requires the expansion of regulatory T cells in culture; this results in a mixed population of regulatory T cells that limits the effectiveness of the transferred cells. Scientists at the NIH have developed a method that promotes the expansion of regulatory T cells that are longer lived, more stable, and more suppressive of the autoimmune response. By supplementing T cell cultures with DNA oligonucleotides, the inventors were able to enrich the regulatory T cell population that enhanced the suppression of the autoimmune response. This method has the potential to more effectively generate regulatory T cells for...
Adoptive cell transfer (ACT) and T-cell receptor (TCR) therapies use lymphocytes that target somatic mutations expressed by tumors cells to treat cancer patients. One of the challenges of these therapies is the identification and isolation of mutation-specific cells and TCRs. While neoantigen specific cells are relatively abundant in the tumor, they are far less common in peripheral blood, a more accessible source of T cells. Researchers at the National Cancer Institute (NCI) have developed a method to isolate neoantigen specific cells or TCRs from selected populations of peripheral T-cells by performing in-vitro stimulation (IVS) on autologous memory T-cells. These cells have been stimulated by their cognate antigens at the tumor site or its draining lymph nodes, and therefore are more relevant for clinical use. The NCI, Surgery Branch, is seeking licensing and/or co-development research collaborations for the development of a method...
Gaucher disease, the most common lysosomal storage disease, is an inherited metabolic disorder in which harmful quantities of the lipid glucocerebroside accumulate in the spleen, liver, lungs, bone marrow and in rare cases in the brain, due to a deficiency of the enzyme glucocerebrosidase (Gba) that catalyses the first step in the biodegradation of glucocerebrosides. Type 1 Gaucher disease is the most common and is distinguished from the other forms of the disease, types 2 and 3, by the lack of neurologic involvement. The clinical features of Type 1 are heterogeneous, vary broadly in clinical severity and affect many organ systems. The major disease manifestations include enlarged spleen and liver, bone lesions, hematologic abnormalities and lung involvement. The disease has also been associated with a sustained inflammatory reaction. Gaucher disease is most prevalent in the Ashkenazi Jewish population with an incidence of...
The current invention embodies a mouse model which is heterozygous for a null allele at the Men1 locus of murine chromosome 19. Men1 has similar exon-intron organization and amino acid identity compared with its human analog MEN1, which has been implicated in the pathogenesis of multiple endocrine neoplasia, type I (MENI). This mouse model has been shown to develop features remarkably similar to those of MEN1, which include tumors of the endocrine pancreas, pituitary, and parathyroids. The model embodied in this invention appears to represent a valuable research tool for use in elucidating the role of the wild-type Men1 allele in tumor formation, and ultimately should aid in the testing of possible therapeutic approaches to human MEN1. Source institute: NHGRI. Inventors: Crabtree, Judy, Collins, Francis.
This technology includes a new chemical scaffold (with lead compound XL5) against hRpn13 that induces apoptosis, which may have clinical efficacy against cancer. The structure of XL5-conjugated hRpn13 guided the design of XL5-PROTAC degrader compounds that exhibit greater efficacy than previous hRpn13-targeting compounds, as evaluated by selectivity for hRpn13, induction of apoptosis, and loss of cell viability. In cells, XL5-PROTACs revealed the presence of a truncated hRpn13 product that binds to proteasomes and is selectively degraded by XL5-PROTACs. The presence of this truncated hRpn13 protein correlates with induction of apoptosis by XL5-PROTACs, providing a previously unknown mechanism of action for hRpn13 targeting. Commercial applications: In the near term, this chemical scaffold against hRpn13 can be used to 1) interrogate hRpn13 function in cells and 2) further development of hRpn13-targeting molecules for clinical...
The Plasmodium parasite has a complex lifecycle during human infection and in the mosquito vector. Most advanced malaria vaccine candidates can confer only partial, short-term protection in malaria-endemic areas. A means of breaking the transmission of malaria to subsequent individuals could prevent a significant amount of human disease. The primary embodiments of this technology are novel compositions of matter that produce enhanced transmission-blocking responses over current transmission blocking vaccines: The inventors designed fusion protein sequences incorporating Pfs230 domain1 (Pfs230D1) at the N-terminus with additional Plasmodium 6-cys domains downstream.. The artificial immunogens retained structured transmission blocking epitopes.. This technology is available for licensing for commercial development in accordance with 35 U.S.C. § 209 and 37 CFR Part 404, as well as for further development and evaluation under a research...
HCV has infected an estimated 3% of the world population in whom viral infection persists for more than two third of the cases, often resulting in life-threatening complications. The standard of care (pegylated interferon alpha-2 plus ribavirin) is efficient in only 50% of treated patients, costly and has numerous side effects. In addition, viral resistance to newly developed drugs -- targeting viral protease or RNA polymerase -- has been described, but no vaccine is yet available. The difficulty in developing HCV vaccines is largely due to the broad sequence-diversity displayed by HCV, the frequent occurrence of viral mutations within immunogenic epitopes in vivo, and the lack of proper standard/definition for viral neutralization. One alternative strategy in HCV-vaccine or drug development comprises measuring viral entry, the first step in viral infection. Such measurements are limited by the available screening systems, in that,...
Rotavirus is a highly contagious, diarrhea-inducing pathogen that annually causes approximately 250,000 deaths worldwide and millions of hospitalizations, especially afflicting infants and young children. One strategy to combat this virus is through vaccination. Continuing safety and efficacy concerns with the currently existing live, oral vaccines against rotavirus have led researchers to search for alternative treatment approaches, such as vaccines containing inactivated rotavirus. This technology describes a method for inactivating rotavirus. Traditional inactivation strategies use chemicals that reduce antigenicity (by altering rotavirus proteins), leading to less protection against the virus. Conversely, this method preserves and/or maintains the integrity of viral particles, leading to greater protection against rotavirus. This strategy has been validated in mice, piglets and cattle and further clinical studies are underway....
A small-molecule class that binds to HIV particles to improve immune response and block viral entry into cells. Problem: 37 million people worldwide currently live with HIV and an estimated 2-3 million new infections occur annually. While antiretroviral therapies do exist for those with the disease, therapy interruption leads to the re-emergence of viral replication and disease progression. Hence, the inability to eradicate viral reservoirs presents a significant hurdle in finding a curative treatment for HIV. Furthermore, issues involving drug toxicity, and the potential for multidrug resistance limits effective therapies. Solution: The small molecule class works by binding to a specific component of HIV particles, preventing them from entering cells. It also sensitizes currently infected cells to our immune system, which is not normally possible during HIV infections. By preventing HIV from entering cells, the small molecules...
Summary: The National Institute on Drug Abuse (NIDA) seeks research co-development partners and/or licensees for a high-powered electronic device and coil that delivers Transcranial Magnetic Stimulation (TMS) pulses as well as the software that controls the device for treating treatment resistant depression, substance use disorders and other CNS disorders. Description of Technology: Transcranial Magnetic Stimulation (TMS) is a non-invasive neuromodulation technique recently cleared by the FDA as a therapy for treatment-resistant major depression, obsessive-compulsive disorder (OCD) and nicotine addiction. Stimulation is produced by passing a brief, strong electric current through a coil placed in close proximity to the patient’s head. The coil generates an electric field inside the patient’s brain, exciting or inhibiting a targeted region. Repetitive high-frequency TMS at 10 Hz (rTMS) was the first protocol cleared by FDA for...
Antibodies are specialized proteins produced by the immune system which target and neutralize foreign materials, such as viruses or bacteria. Antibodies have a variety of useful applications in diagnostics, therapeutics, and as research reagents. Despite their widespread use there is no standard method to produce antibodies, and currently available methods are labor and time intensive. CDC scientists have developed a rapid method for producing antibodies with swappable DNA fragments using a PCR based assay. This method avoids lengthy cloning steps, reducing the time to produce an expression ready antibody cassette from a few days to a few hours. Further, this method uses readily available reagents and equipment. Antibodies produced using this method could be sold as diagnostics, therapeutics, or research reagents. This method could also be used to provide antibody manufacturing services. Potentially, host cells could be transfected...
Tumors can develop unique genetic mutations which are specific to an individual patient. Some of these mutations are immunogenic; giving rise to autologous T cells which are tumor-reactive. Once isolated and sequenced, these neoantigen-specific TCRs can form the basis of effective adoptive cell therapy cancer treatment regimens; however, current methods of isolation are inefficient. Moreover, the process is technically challenging due to TCR sequence diversity and the need to correctly pair the a and b chain of each receptor. Thus, there is an urgent need for more robust methods of identifying paired sequences of mutation-specific TCRs for cancer immunotherapy. Researchers at the NCI have developed an efficient method for isolating the paired sequences of TCRs. Using single-cell methodology, next generation sequencing and custom bioinformatics software, the researchers can isolate full-length TCR α and β chain sequences from...
There is no scalable platform today that can efficiently generate peptide-specific binders to intracellular cancer targets and translate them into broadly applicable cell therapies across diverse HLA types.
The present invention is directed to a synthesis of a dual-target inhibitor of cannabinoid-1 (CB1R) receptor and inducible nitric oxide synthase, and more specifically, to an improved process for synthesis of (S,1E,NE)-N-(1-aminoethylidene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide. Commercial applications: This new route and process to synthesis S-MRI1867 without chromatography can be easily adapted to GMP manufacture to produce S-MRI1867 for clinical studies and further commercial production. Competitive advantages: This process to produce S-MRI1867 is more time efficient and cost effective. It gives a new version to synthesis the compounds with the core structure similar to S-MRI1867. Source institute: NCATS. Inventors: Huang, Junfeng, Alimardanov, Asaf.
The zinc finger protein ZFP36L2 has been shown by the inventors to play an essential role in hematopoiesis, a process that is dysregulated in hematological cancers, anemia, and other conditions. Thus, ZFP36L2 has promise for use in a diagnostic test to detect abnormal hematopoiesis, or as a target for the development of therapeutics to treat abnormal hematopoiesis. Hematopoiesis is the formation of blood cellular components, through the differentiation of hematopoietic stem cells into lineages with a variety of roles, such as carrying oxygen, immune function, and blood clotting. Abnormally high hematopoiesis can be caused by hematological cancers such as leukemia or lymphoma, or by other myeloproliferative disorders. Abnormally low hematopoiesis can be caused by diseases such as anemia, thrombocytopenia, or myelodysplastic syndrome, and is often a secondary symptom of other conditions, such as cancer, infection, or dialysis. The...
Cataract is the most common cause of blindness worldwide, with an estimated 25 million blind and 119 million visually impaired individuals worldwide. Over 20 million adults in the US alone are currently diagnosed with cataracts making this disease a major health concern. The incidence of cataract increases with age and a number of etiologic factors have been proposed in the pathogenesis of age-related cataract in humans including genetic factors, environmental factors and metabolic and biochemical changes in the crystalline lens. Ultraviolet radiation exposure and oxidative injury to the lens has been considered by some to be one of the most important factors in cataractogenesis. The present therapy of choice for cataract is laser surgery. Experimental investigation of human age-related cataract is hindered by a lack of available animal models of cataract. Several laboratory mice strains with heritable cataracts have been studied...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for viral peptide (CE1)-based therapeutics for HCC prevention and treatment. Description of Technology: Hepatocellular carcinoma (HCC) is a common and aggressive primary liver cancer. It develops mainly from at-risk individuals with underlying chronic liver diseases, such as hepatitis and cirrhosis. HCC is a leading cause of cancer-related death worldwide and its global incidence and mortality rate continues to rise. The current methods for early detection, surveillance and treatment are suboptimal due to complex etiologies and intricate tumor biology. Through serological profiling across three independent cohorts, researchers at the National Cancer Institute (NCI) have identified a common epitope (CE1) shared among protective viral antigens enriched in healthy individuals compared to HCC patients. A synthetic CE1 peptide was...
Technology Overview: Tissues within the body experience mechanical perturbations across multiple force magnitudes and length scales, from mechanotransduction at the cell level to the dynamics of load-bearing joints. These forces not only maintain tissue homeostasis, but can also initiate degenerative processes when applied at supra-physiologic levels.... Inventors: George Dodge, Daeyeon Lee, Robert Mauck.
Selective A3AR agonists are sought as potential agents for treating inflammatory diseases, chronic pain, cancer and non-alcoholic steatohepatitis (NASH). NIDDK investigators have invented new chemical composition as positive allosteric modulators (PAMs) of the A3AR. These chemical compounds contain sterically constrained, bridged modifications and cycloalkyl rings of various sizes, as well as modifications of the 4-arylamino group. The compounds have added three-dimensionality to otherwise flat molecules, which helps distinguish their positive (desired) and negative (undesired) pharmacological effects on the action of A3AR agonists. Unlike agonists that have side effects, PAM action can be event- and site-specific because adenosine is endogenously elevated in response to localized distress signals within the body. Source institute: NIDDK. Inventors: Jacobson, Kenneth, Fallot, Lucas, Ravi, Rama, Pradhan, Balaram.
The invention described and claimed in this patent application relates to the delivery of heterologous nucleic acids or genes to particular target cells. In particular, the application relates to methods of delivering a heterologous nucleic acid or gene of interest to particular target cells using Adeno-Associated Virus of serotype 4 (AAV4). The particular target cells identified are the ependymal cells of the brain. The methods described herein may be useful in carrying out gene therapy for diseases of the brain or central nervous system. Source institute: NHLBI. Inventors: Kotin, Robert, Safer, Brian, Davidson, Beverly, Chiorini, John.
The invention described and claimed in this patent application provides for novel vectors and viral particles which comprise adeno-associated virus serotype 5 (AAV5). AAV5 is a single-stranded DNA virus of either plus or minus polarity which, like other AAV serotypes (e.g., AAV4, AAV2) requires a helper virus for replication. AAV type 2 has the interesting and potentially useful ability to integrate into human chromosome 19 q 13.3-q ter. This activity is dependent on the non-structural, Rep, proteins of AAV2. The Rep proteins of AAV types 2 and 5 are dissimilar and are not able to substitute in DNA replication of the heterologous serotype. AAV5 offers several advantages which make it attractive for use in gene therapy: 1. increased production (10-50 fold greater than AAV2); 2. distinct integration locus when compared to AAV2; 3. Rep protein and ITR regions do not complement other AAV serotypes; and 4. appears to utilize different cell...
The invention described and claimed in this patent application is related to the delivery of heterologous nucleic acids or genes to particular target cells. In particular, the application relates to methods of delivering a heterologous nucleic acid or gene of interest to particular target cells using an Adeno-Associated Virus of serotype 5 (AAV5). The particular target cells identified include the alveolar cells of the lung and cerebellar and ependymal cells of the brain. The methods described herein may be useful in carrying out gene therapy related to diseases of the brain or central nervous system and the respiratory tract. Source institute: NHLBI. Inventors: Davidson, Beverly, Kotin, Robert, Zabner, Joseph, Chiorini, John.
ADP-ribosylation is important in many cellular processes, including DNA replication and repair, maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. Poly-ADP-ribose is important in a number of critical physiological processes such as DNA repair, cellular differentiation, and carcinogenesis. Until recently, only one human enzyme, PARG, had been identified that degrades the ADP-ribose polymer. Another ADP-ribose, O-acetyl-ADP ribose, is formed via the deacetylation of proteins, such as acetyl-histone, by proteins in the Sir2 family. Sir2 proteins have been implicated in regulation of chromatin structure and longevity. The NIH announces the discovery of a novel PARG-like enzyme, ARH3. ARH3 possesses PARG activity, yet is structurally distinct from PARG. ARH3 also hydrolyzes O-acetyl-ADP-ribose, and is the only protein recognized to date with such activity. ARH3 thus...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for the development of AOAH as a cancer immunotherapy. Description of Technology: Immune CheckPoint Inhibitors (ICIs) and T-cell based therapies are part of the emerging immunology-based therapies being used to treat cancers. However, the efficacy of ICI therapies can be limited and a substantial portion of patients develop resistance or tolerance to treatment. T-cell based cancer immunotherapies have only been approved for hematological cancers. They are suboptimal in solid tumor cancers due to physical barriers and the immuno-suppressive tumor microenvironment. Thus, additional therapies and strategies are needed to improve efficacy and expand the types of cancer amendable to treatment. Scientists at the National Cancer Institute have identified a secreted lipase, Acyloxyacyl Hydrolase (AOAH), produced by cells such as macrophages...
We have isolated, cloned, and characterized multiple T cell receptors (TCRs) from human donors specific for common mutations in KRAS and restricted to highly prevalent HLA types. These TCRs, protected by a Penn provisional filing, are suitable for T cell engineering for the adoptive immunotherapy of cancer patients of select HLA types and tumors expressing particular KRAS mutantions. The comprehensive bioinformatics, biochemical and immunological assessment of these TCRs is in press (Bear et al, Nature Communications). Problem: Mutations of the KRAS gene (mKRAS) serve as the driving oncogene in multiple cancers including lung cancer, colon cancer, and up to 95% of pancreatic ductal carcinoma. KRAS inhibitors have garnered FDA approval, proving the value of KRAS as a cancer target. However, there is no approach to target KRAS immunologically. Solution: We have shown that peptides derived from mKRAS are expressed on HLA molecules on the...
This technology represents a significant advancement in the field of rabies prevention, focusing on the development of highly potent rabies-neutralizing monoclonal antibodies (mAbs) for use in postexposure prophylaxis (PEP). With two mAbs, F2 and G5a, displaying exceptional neutralizing titers of 1154 and 3462 International Units (IUs) per milligram, respectively, these antibodies have the potential to offer enhanced protection against rabies when administered alongside rabies vaccines. The production of these mAbs involves genetic engineering of mammalian cell lines, enabling their consistent and efficient production. While the in vitro results are promising, rigorous in vivo animal protection assays are necessary to confirm their effectiveness in providing protection against rabies, ultimately offering a promising solution to a disease that remains almost invariably fatal once clinical symptoms develop. Commercial applications:...
Approximately 30,000 patients are diagnosed with renal cell carcinoma (RCC) each year in the United States, and an estimated 12,000 patients die of this disease. Most patients are diagnosed with advanced local disease or metastatic disease. Metastatic RCC carries a poor prognosis with median survivals in the range of 10-12 months. Drugs that inhibit VEGF receptor tyrosine kinases such as Sorafenib and Sunitinib have recently been approved by the FDA to treat metastatic RCC. Although a significant percentage of patients will achieve a partial response or disease stabilization with these agents, complete responses are rare and disease progression eventually ensues. RCC is unusual among solid tumors as it appears to be susceptible to immunotherapy. Cytokines such as IL-2 and IFN-alpha nonspecifically stimulate the immune system resulting in disease regression. Unfortunately, these drugs achieve success in only a minority (15-20%) of the...
Human papillomavirus (HPV) has been associated with the cause of several cancer types, including cervical, anal, and head and neck cancers. There has been great success in preventing HPV infections with the development of prophylactic HPV vaccines, Gardasil and Cervarix. However, these vaccines have only been shown to prevent HPV infection and not treat those already infected with HPV. These vaccines elicit antibody responses to late HPV genes, and thus would not be effective in treating established tumors. To date, no therapeutic HPV vaccine has been approved by the FDA, and there is an unmet need for therapeutic vaccines for the treatment of cervical, anal, and head and neck cancers. One approach in the development of HPV therapeutic vaccines is the use of agonist epitopes that would elicit enhanced cytotoxic T-lymphocyte (CTL) responses capable of lysing human tumor cells expressing native HPV epitopes. Researchers at the National...
The National Cancer Institute is seeking parties interested in licensing human monoclonal antibodies (mAbs) that bind to death receptor 4 ("DR4"). The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its functional receptors, DR4 and DR5, have been recognized as promising targets for cancer treatment. Therapeutics targeting TRAIL and its receptors are not only effective in killing many types of tumors but they also synergize with traditional therapies, and show efficacy against tumors that are otherwise resistant to conventional treatments. Researchers at NCI have developed two human monoclonal antibodies (mAbs) that bind to death receptor 4 ("DR4"). One of the mAbs is agonistic and inhibits the growth of ST486 cells with IC50 of about 10nM. The two mAbs were selected from a human phage-displayed Fab library by panning against a recombinant DR4 extracellular domain. Therefore the two mAbs are fully human....
Tetracycline-responsive transcriptional activator driven by the liver-specific mouse albumin promoter (Alb-tTA). The E. Coli tetracycline operon regulatory system was used to generate a liver-specific transcription activation system that was inhibited by tetracycline. The transcription activator was a fused protein consisting of a tetracycline repressor gene (tetR) that was only active in the presence of tetracycline and a herpes simplex virus protein (VP-16) transcription activating domain. Transcription was induced only in the absence of tetracycline (Tet-Off). A liver-specific promoter such as mouse albumin determined that the tetracycline-regulated transcriptional activator (tTA) would be expressed specifically in liver. To study the effect of the transcription activator on a target gene (for example, Simian Virus 40 (SV4) large tumor (T) antigen (TAg)) specifically in liver, Alb-tTA mice were mated with transgenic mice in which...
The invention relates to compositions of matter and methods for treating arthritis by modulating Tumor Necrosis Factor Alpha (TNF-alpha) signaling. TNF-alpha plays a key role in the pathogenesis of numerous diseases including rheumatoid and septic arthritis, and other autoimmune and inflammatory diseases. TNF-alpha mediates its effects through receptors that contain a Pre-ligand Assembly Domain (PLAD). The inventors have discovered compounds that interfere with PLAD can block the effects of TNF-alpha in vitro. Treatment of mice with these compounds in vivo ameliorated disease in several models of arthritis. Therefore, the compositions and methods of the current invention may lead to novel arthritis treatments. Source institute: NIAID. Inventors: Lenardo, Michael, Chan, Francis, Siegel, Richard.
Nanoparticles for potent encapsulation and delivery of therapeutic molecules for prenatal fetal therapy in the amniotic sac Problem: Many prenatal genetic diseases suffer from ineffective postnatal treatments. For this reason, therapies that are delivered to the fetus before birth hold promise to treat diseases prior to or in the early stages of pathology and reduce disease burden, morbidity, and mortality. Viral vectors can deliver nucleic acids to the fetus for prenatal protein and enzyme replacement; however, they have limitations regarding immunogenicity, genomic integration, and repeat dosing. Non-viral nucleic acid delivery methods avoid these risks yet face challenges with rapid nucleic acid degradation and hindered transport into cells. Solution: A lipid nanoparticle nucleic acid delivery system was developed that remains stable upon delivery in utero and potently delivers nucleic acid material intracellularly, providing...
A flexible toolkit for human gene editing, activation, and repression that can be applied in orthogonally and in various disease models. Problem: There is increasing demand for technologies that can simultaneously edit the genome and regulate the transcriptome without relying on toxic double-stranded breaks. Currently, treating complex diseases such as cancer require correcting genomic point mutations while simultaneously activating or repressing secondary genes that are deregulated. These independent tasks require the co-delivery of multiple large effectors, drastically exceeding the strict packaging limits of modern clinical vectors like AAVs. Therefore, there is a dire need for a single, compact tool that provides orthogonal control over gene editing and expression. Such a unified platform would bypass viral packaging bottlenecks, eliminate CRISPR/Cas9-induced cytotoxicity, and unlock next-generation precision therapies. Solution:...
Summary: Researchers at the NCI seek licensing and/or co-development research collaborations for anti-viral Griffithsin (GRFT) proteins. Description of Technology: Virus entry into a susceptible host cell is the first step in the formation of all viral diseases. Controlling viral infections by disrupting viral entry is advantageous for antibody-mediated neutralization by the host’s immune system and as a preventive and therapeutic antiviral strategy. Plant-derived carbohydrate-binding proteins (lectins) have emerged as a new class of antiviral biologics by taking advantage of a unique glycosylation pattern only found on the surface of viruses. This technology describes the lectin, Griffithsin (GRFT), isolated from red algae. GRFT shows significant broad-spectrum anti-viral activity making it a promising agent for use as a general microbicide that can prevent viral transmission and as a therapeutic against enveloped virus-mediated...
A unique platform that combines comprehensive tumor antigen discovery with direct validation of HLA-presented peptides, bridging the gap between predicted targets and clinically actionable opportunities in immunotherapy and diagnostics.
Simple, plug-and-play biodegradable lipids that form highly potent lipid nanoparticles (LNPs) for CRISPR mRNA delivery, outperforming benchmark gene-editing systems. Problem: CRISPR therapies can permanently correct disease-causing genes, but today's CRISPR delivery systems are either too risky or not potent enough. Viral vectors raise red flags on immunity, safety, cost, and manufacturing, while current LNPs require very high doses to achieve meaningful editing. This potency gap limits how broadly LNP gene editing can safely be applied across genetic diseases. Furthermore, LNP limitations slow development timelines because companies must repeatedly re-engineer new delivery chemistries for each specific therapy. Solution: The inventors have developed a two-component technology: "plug-and-play" combinatorial chemistry approach that builds biodegradable, ionizable lipids in a single, high-yield chemical reaction. From a 500-lipid...
Problem: Degenerative diseases of the retina such as age-related macular degeneration (AMD) are the leading cause of vision loss and blindness. Approximately 120 million people worldwide suffer from AMD. There is a need to further understand the pathogenesis of retinal degeneration in order to develop new therapeutics to prevent and treat these diseases.... Problem: Degenerative diseases of the retina such as age-related macular degeneration (AMD) are the leading cause of vision loss and blindness. Approximately 120 million people worldwide suffer from AMD. There is a need to further understand the pathogenesis of retinal degeneration in order to develop new therapeutics to prevent and treat these diseases. Solution: Iron has been implicated in the pathogenesis of several degenerative diseases including those affecting the retina (e.g. AMD) and in neurodegenerative diseases such as Alzheimer’s Disease and Parkinson’s Disease. Previous...
A two-step, high yield, method for synthesizing naturally derived, Hemi-Phorboxazole A analogs Problem: (+)-Phorboxazole A and B, extracted from the sponge Phorbas sp., display extraordinary anti-proliferative activity against National Cancer Institute’s (NCI) panel of 60 human tumor cell lines. Due to their complex structures, the reported syntheses of Phorboxazole A and B analogues consist of 100 total steps with an average yield of 4%. The limited availability of these compounds has precluded the evaluation of their biological activity. As such, there is a need for improved syntheses of these compounds, featuring fewer steps while providing higher yield and selectivity. Solution: Researchers in the Smith Lab have developed a two-step, high yield (85%) method for preparing Hemi-Phorboxazole A from a known precursor. Two analogues of Hemi-Phorboxazole were designed and synthesized in this manner. One analogue exhibits...
A combinatory formulation for oral care products that enhances antimicrobial specificity, anti-plaque potency and prevents tooth decay. Problem: Tooth decay (dental caries), caused by the destruction of the outer layer (enamel) of teeth by bacteria in biofilms, affects nearly half of the global population and remains the most prevalent chronic disease in children and adults. Left untreated, it can cause toothache, infection with systemic complications, and tooth loss. There are no effective prevention measures for high-risk individuals where bacterial biofilms on the surface (known as dental plaque) rapidly accumulate. The leading prevention formulations include stannous fluoride (SnF2), which is unstable, reducing its antibacterial and caries-preventive activities. Solution: Combining SnF2 with Ferumoxytol (Fer) more efficiently kills cavity-causing bacteria and disrupts biofilm formation than SnF2 alone while creating a...
Modafinil has attracted attention for the treatment of cognitive dysfunction in disorders such as attention-deficit/hyperactivity disorder (ADHD) as well as cocaine and methamphetamine dependence. However, modafinil has relatively low affinity for binding to the dopamine transporter (DAT) to block dopamine reuptake, and is water-insoluble, thus requiring large doses to achieve pharmacological effects. Investigators at the National Institute of Drug Abuse have synthesized a series of modafinil analogues that have higher affinity for the dopamine (DAT), serotonin (SERT) and/or norepinephrine (NET) transporters and improved water solubility. These novel analogues present the advantage of higher potency, which may translate into lower effective doses and better bioavailability over modafinil. Competitive Advantages: Higher affinity for monoamine transporters (DAT, SERT, and NET) compared to modafinil. Analogues have lower effective doses....
Vascular Endothelial Growth Factor-A (VEGF-A) is an angiogenic agent that drives blood vessel formation in solid tumors and other diseases, such as macular degeneration and diabetic retinopathy. Several therapies that target the ability of VEGF to stimulate angiogenesis have been approved. These therapies regulate VEGF-A activity by binding VEGF-A, thereby blocking VEGF-A from binding to its receptor on target cells. This technology utilizes a different approach to regulating VEGF-A activity by providing a VEGF-A protein antagonist that is produced by engineering native VEGF-A protein. The engineered VEGF-A protein disrupts heparin sulfate proteoglycan binding to the VEGF-A/VEGF receptor complex, an activity that is essential for the angiogenic properties of native VEGF-A. The antagonist has a binding affinity for both FLT-1 (VEGFR-1) and KDR/FLK-1 (VEGFR-2) that is equivalent to that of native VEGF-A and specifically antagonizes all...
This technology includes a first-in-class synthetic peptide, angubindin-1, designed to temporarily relax the blood-brain barrier (BBB)—the tightly sealed network of brain blood vessel cells that normally blocks most drugs—from the inside. By binding the tricellular tight-junction protein angulin-1/LSR, the peptide creates a reversible “molecular doorway” that lets cancer medicines such as liposomal doxorubicin (Doxil®) reach tumors in the central nervous system (CNS). In rodent models of malignant glioma, co-administration of angubindin-1 increased drug penetration into the brain, cut tumor volume, and significantly prolonged survival compared with chemotherapy alone. The opening of the BBB is short-lived and spatially restricted, minimizing exposure of healthy brain tissue and avoiding the hardware, ultrasound, or high-dose osmotic agents required by competing methods. Commercial applications: Adjunct to standard-of-care chemotherapy...
This molecular probe may serve as a companion tool to identify and stratify patient populations based on the prevalence of the target A 3 adenosine receptors. Small molecule drugs, A 3 AR-selective agonists, are currently in advanced clinical trials for the treatment of hepatocellular carcinoma, autoimmune inflammatory diseases, such as rheumatoid arthritis, psoriasis, and dry eye disease, and other conditions. Commercial applications: Tools to study prevalence of this receptor on neutrophils, a predictor of response to agonist drugs.. Competitive advantages: Avoids the use of radioisotopes in this part of the R&D process.. Source institute: NIDDK. Inventors: Jacobson, Kenneth.
Leishmania parasites are transmitted to their vertebrate hosts by infected phlebotomine sand fly bites. Sand fly saliva is known to enhance Leishmania infection, while immunity to the saliva protects against infection. This invention claims nine major salivary proteins from the sand fly vector of Leishmania major , Phlebotomus papatasi , nucleic acids encoding the proteins, vaccines comprising the proteins and/or nucleic acids, and methods of producing an immune response to prevent Leshmaniasis . The inventors have shown that one of these salivary proteins was able to protect vaccinated mice challenged with parasites plus salivary gland homogenates (SGH). A DNA vaccine containing the cDNA for the same protein provided this same protection. Protection lasted at least 3 months after immunization. The vaccine produced both intense humoral and delayed-type hypersensitivity (DTH) reactions. B cell-deficient mice immunized with the plasmid...
Most early work on CD133 was carried out using one of two monoclonal antibodies (mAbs), AC133 and AC141, which recognize an undefined glycosylated epitope of CD 133. Researchers from NCI's Pharmacodynamic Assay Development and Implementation Section generated novel anti-human CD133 monoclonal antibodies from large extracellular domain loops of CD133 using peptide residues selected from the native extracellular domains of CD133 protein as an immunogen. They selected sequences for immunization that do not overlap with known glycosylation sites. Peptide antigens comprising the amino acids in the extracellular domain were synthesized and conjugated to carrier proteins as the immunogen. A key step was screening for specificity using peptides and expressed recombinant extracellular domains of CD133. The resulting antibodies recognize both glycosylated and non-glycosylated regions of the cognate antigen. The inventors have demonstrated the...
Description of Technology: Neuroblastomas are the most common extracranial solid tumors in pediatric patients, with 700-800 new cases annually in the United States. Metastatic neuroblastomas have a five-year survival rate of 50% and account for 15% of all pediatric cancer deaths. As such, more effective treatments against high-risk neuroblastomas are urgently needed. Glypican-2 (GPC2) is a cell surface protein that is highly expressed in neuroblastomas and other cancers, including medulloblastoma, retinoblastoma, small-cell lung cancers, uterine carcinosarcomas and high-grade gliomas, which makes GPC2 an attractive candidate for targeted therapy in solid tumors. Researchers at the National Cancer Institute’s (NCI) Center for Cancer Research have developed a novel Chimeric Antigen Receptor (CAR) specific for GPC2 that includes a potent anti-GPC2 antibody CT3 and a CD28 hinge and transmembrane domains. CT3 has been shown to specifically...
The National Cancer Institute seeks parties interested in collaborative research to further co-develop monoclonal antibodies for the treatment of mesothelin-expressing cancers. The antibody was able to inhibit tumor growth in mouse xenograft models, and corresponding immunotoxins were able to inhibit tumor cell growth in vitro Mesothelin is a cell surface protein that is highly expressed in aggressive cancers such as malignant mesothelioma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, cholangiocarcinoma, bile duct carcinoma and gastric cancer. This selective expression makes mesothelin an excellent candidate for targeted therapeutics such as monoclonal antibodies (mAbs) and corresponding chimeric molecules. Unfortunately, current anti-mesothelin mAb candidates have drawbacks, such as competition with a serum protein (MUC16/CA125) for binding to mesothelin, the formation of neutralizing antibodies because they are...
This invention describes methods and compositions of peptides that inhibit the binding of Plasmodium falciparum ( P. falciparum ) to erythrocytes. Malarial parasites enter the red blood cell through several erythrocyte receptors, each being specific for a given species of Plasmodia . For P. falciparum , the erythrocyte binding antigen (EBA-175) is the ligand of the plasmodia merozoites that interacts with the receptor glycophorin A on the surface of red blood cells. Inhibiting this ligand/receptor interaction is one method of preventing further malarial attacks and is an active area of vaccine research. This invention describes another specific peptide and antibodies that inhibit this ligand/receptor binding, thus is a potential source for vaccine development. The peptide described herein is a paralogue of EBA-175, identified as EBP2. Further, the invention includes antibodies and peptides that are specific for the claimed paralogue....
Immortalization of plasma cells leads to Multiple Myeloma (MM). Signaling Lymphocyte Activation Molecule F7 (SLAMF7) is highly expressed on the malignant plasma cells that constitute Multiple Myeloma. The expression of SLAMF7 by MM cells and lack of expression on nonhematologic cells makes SLAMF7 a promising target for chimeric antigen receptor (CAR) T cell therapies for the treatment of MM. In addition to expression on normal and malignant plasma cells, SLAMF7 is also known to be expressed on a variety of other leukocytes including most natural killer (NK) cells, some CD8+ T cells, a small fraction of CD4+ T cells, NKT cells, some monocytes, and some dendritic cells. Therefore, a CAR targeting SLAMF7 may also eliminate SLAMF7-expressing leukocytes such as NK cells and dendritic cells, which could increase the risk of unwanted side effects from cancer therapies, such as infections. As a way to overcome such unwanted side effects, a...
Several novel tropolone derivatives have been identified that inhibit HIV-1 RNase H function and have potential for anti-viral activity due to reduced cellular toxicity. Inhibiting RNase H function is a potential treatment for many viral infections, since RNase H function is essential for viral replication for many pathogenic retroviruses such as HIV-1 and HIV-2. Although many hydroxytropolone compounds are potent RNase H inhibitors biding at the enzymatic active site, they are limited as therapeutic candidates by their toxicity in mammalian cells. The toxicity thought to be a result of inhibition of multiple essential mammalian metalloenzymes. We reasoned that the potential beneficial application of tropolone RNase H inhibition might be of therapeutic use if the toxic effects in mammalian cell were eliminated. By selectively adding steric bulk to add new drug-enzyme contacts for the RNase H active site, a number of novel compounds,...
Description of Technology: This technology describes additional methods of using the griffithsin anti-viral polypeptides described in related NCI invention (reference number E-106-2003). Specifically, this invention describes the use of GRFT to inhibit viral infection of hepatitis C viral infection, a severe acute respiratory syndrome (SARS) viral infection, an H5N1 viral infection, or an Ebola viral infection. Issued patents: US 8,088,729 (Jan. 3, 2012) and foreign rights in France, Germany, Ireland, United Kingdom, Switzerland (all granted) Potential Commercial Applications: Microbicide that can prevent viral transmission. Therapeutic against enveloped virus-mediated diseases. Competitive Advantages: Highly Potent Broad-Spectrum Antiviral Lectin. Superior in vitro and in vivo antiviral activity with minimum host toxicity against a variety of clinically relevant, enveloped viruses.. Source institute: NCI. Inventors: O'Keefe, Barry,...
Tuberculosis (TB) is an infectious disease that typically affects the lungs. Current therapies include a panel of antibiotics given over a range of 6-9 months. As a result of the expense of treatment, the extended timeframe needed for effective treatment, and the scarcity of medicines in some developing countries, patient compliance with TB treatment is very low and results in multi-drug resistant TB (MDR-TB). There remains a need for a faster, more effective treatment for TB. Short, metabolically stable, cell-penetrating lipopeptide mimics of conserved regions of IL-10 and STAT3 inhibit those proteins’ signaling to become a host-directed therapy against TB. Intrapulmonary aerosol delivery of the peptides results in increased bactericidal capacity of the host immune system (e.g., increased nitric oxide, NADPH oxidase, lysozyme activities). Researchers at the National Cancer Institute's Cancer and Inflammation Program developed peptide...
This technology includes a new class of synthetic peptides that activate Lipoprotein Lipase (LPL), a key plasma enzyme that lowers triglycerides, by displacing apoC-111, a potent inhibitor of LPL. ApoC-11 is a known activator of LPL, whereas ApoC-111 inhibits LPL and raises triglycerides either directly by blocking lipolysis and or by preventing hepatic uptake of lipoproteins. Both apoC-II and apoC-III have to bind to the surface of a lipoprotein particle to mediate their effects. We discovered that we can displace apoC-III from lipoproteins and improve lipolysis by adding short synthetic peptide mimetics of apoC-II. These peptides are described in another EIR. Anti-sense therapy against apoC-111 has been shown in late-stage clinical trials to be useful for a wide variety of causes of hypertriglyceridemia, including LPL deficiency, thus our new peptides that antagonize apoC-III can be an alternative approach. Commercial applications:...
Fms-like tyrosine kinase 3 (FLT3) is a cytokine receptor which belongs in the receptor tyrosine kinase class III. FLT3 is expressed on the surface of many hematopoietic progenitor cells and plays an important role in hematopoietic stem/progenitor cell survival and proliferation. It is often overexpressed in acute lymphoblastic leukemia (ALL) and is frequently mutated in acute myeloid leukemia (AML). The standard therapies for ALL and AML are still suboptimal for many patients, especially pediatric. In certain types of ALL or AML, the survival rate is less than 40 and 60%, respectively. There remains a need for effective treatments for ALL and AML. Inventors have discovered five high-affinity, fully human monoclonal antibodies (m1006, m1007, m1008, m1009, and m1012) targeting FLT3. Since the antibodies are fully human, they are expected to have lower toxicity and will not require humanization or affinity maturation for clinical...
Lyssaviruses are single-stranded RNA viruses that cause rabies and rabies-like diseases in mammals. According to the World Health Organization, human rabies caused by the classical rabies virus continues to be almost 100% fatal once clinical symptoms of rabies appear, with no specific treatment available anywhere in the world. CDC researchers have identified lyssavirus-specific antibodies for the treatment and prevention of rabies in humans post-exposure. They have also developed a method using a naïve antibody phage display library to identify phage clones that bind recombinant rabies virus or cells from multiple lyssaviruses. The sequence of domain antibodies specific for lyssaviruses can be used to engineer a monoclonal antibody for targeting in human rabies post-exposure prophylaxis or antiviral therapy of clinical rabies (when a patient manifests with rabies symptoms such as headache, confusion, agitation, delirium, etc.). This...
Technology Overview: Acute myeloid leukemia (AML) is a major form of acute leukemia in elder adults. The treatment of AML has changed little in the past decades and the overall 5-year survival rate remains very poor in the AML patients. AML relapsed from chemotherapy is highly aggressive with poor prognosis. While adaptive cell therapy via chimeric... Applications: CAR-T cell therapies for AML Antibody-drug conjugates targeting AML cells Potential use for AML diagnosis, treatment monitoring, and imaging Inventors: Xianxin Hua.
Technology Overview: Neuroendocrine tumors (NETs) pose serious threats to patients’ well-being as malignant diseases, and most patients with metastatic NETs succumb to the disease. Using Sequential Tumor-related Antibody and antigen Retrieving (STAR) technology Dr. Xianxin Hua, MD, PhD at the University of Pennsylvania Medical School and his... Applications: CAR-T cell targeting to NET cells Conjugation with anticancer drugs to target NET cells Tumor diagnosis, treatment monitoring, and imaging Inventors: Xianxin Hua.
This technology includes antibodies for TMC1 protein as a treatment for hearing loss. TMC1 is one of the common genes causing hereditary hearing loss. Our laboratory used synthetic peptides corresponding to the TMC1 protein to immunize rabbits. The resulting antisera were shown to bind to TMC1 protein expressed in heterologous expression systems. TMC1 protein is required for the transduction of sound into electrical impulses in inner ear sensory cells. Commercial applications: Future treatment for hearing loss. . Competitive advantages: Antibodies that specifically bind TMC1 protein are difficult to make; there are commercially available antibodies to TMC1 but they do not appear to be as sensitive or specific or as carefully characterized as the antibodies generated in this invention. . Source institute: NIDCD. Inventors: Griffith, Andrew, Makishima, Tomoko, Labay, Valentina.
This technology includes monoclonal antibodies (mAb) that specifically and with high affinity bind the final complement components C3dg and C3d (subsequently referred to as C3d), which can be used to kill tumor cells that carry C3d on their cell surface. We show that tumor cells of patients treated with the therapeutic anti-CD20 mAb ofatumumab carry C3d on the cell surface and can bind and be killed by addition of anti-C3 mAbs. In contrast, further addition of more ofatumumab has only minimal effects. This invention is a novel therapeutic concept to enhance the efficacy of therapeutic antibodies and the specific mAbs to achieve this goal. In a "one-two punch" approach, administration of a first tumor antigen-specific mAb that kills some but not all tumor cells is followed by an anti-C3d mAb that targets the C3d deposited on the tumor cells. Commercial applications: Therapy for multiple forms of cancer. Competitive advantages: Novel...
Mesothelin is a cell surface protein that is highly expressed in aggressive cancers such as malignant mesothelioma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, cholangiocarcinoma, bile duct carcinoma and gastric cancer. As a result, mesothelin is an excellent candidate for tumor targeted immunotherapeutics. However, the antibodies against mesothelin that are available for clinical trials are of murine origin. These antibodies have the potential to elicit immune responses in patients, which may adversely affect the ability to provide patients with repeated doses. Thus, the clinical application of the antibodies may be limited. In order to address the issue of immunogenicity in patients, NIH inventors have generated anti-mesothelin antibody variable fragments (Fv) of human origin. These antibody fragments (HN1 and HN2) have the ability to efficiently recognize mesothelin on the surface of numerous cancer cells. As a...
Technology Overview: Screening platform for identification of potent and specific nanobodies for (i) directing CAR-T cells to cancer cells, (ii) drug conjugation, or (iii) tumor imaging or diagnosis. Identification of antibodies capable of mediating CAR-T killing is challenging due to several reasons. First, the antibody has to have certain affinity... Applications: Identification of tumor-specific nanobodies that can be used for: CAR-T cell targeting Conjugation with anticancer drugs Tumor diagnosis, treatment monitoring, and imaging Inventors: Xianxin Hua.
Technology Overview: While antibody therapeutics have proven to be successful in recent years, they are not without drawbacks. The large size of antibodies can prevent their effective use against certain cancers, as well as prevent them from crossing the blood-brain barrier. Additionally, many antibodies require post-translational modifications and... Inventors: Mark Greene.
A method to combine two or three monoclonal antibodies (mABs) into one treatment to successfully bind to multiple cancer cell surface epitopes and promote targeted degradation by phagocytosis. Problem: Phagocytosis of ‘self’ cells is generally inhibited by a key macrophage checkpoint interaction between SIRPα on the macrophage and CD47 on all cells including cancer cells. Tumor cell engulfment can nonetheless be driven by anti-tumor monoclonal antibodies that bind Fc-receptors on macrophages (e.g., anti-CD20 in lymphoma). While the mAB-based therapies address critical aspects of cancer cell survival mechanisms, they often engage only one anti-cancer mechanism, increasing the probability of treatment-resistance disease. Further challenges for macrophage checkpoint blockade in solid tumors include low permeation of anti-CD4721 relative to the potency of inhibitory signaling as well as on-target, off-tumor binding of antibodies to...
This CDC developed invention pertains to Streptococcus pneumoniae protein "pneumococcal fimbrial protein A (PfpA)," as well as the encoding pfpA gene. S. pneumoniae linked pneumococcal disease is prevalent among the very young, the elderly and also immunocompromised individuals. This invention covers the breadth of directly PfpA-related technology that might be employed for development of diagnostic tests for S. pneumoniae and/or vaccines directed against the pathogen. In addition to the the intellectual property protected amino acid sequence and encoding plasmid, monoclonal antibodies and corresponding hybridomas are also available. Commercial applications: Screening diagnostic young, elderly and immunocompromised patients for possible S. pneumoniae infection. Pneumococcal disease vaccine development or refinement. Competitive advantages: Easily adapted to a high-throughput assay for mass screening purposes. Can be formatted as an...
Summary: NCI is seeking parties interested in co-developing and/or licensing therapeutic antisense oligonucleotides that target cell migration and cancer metastasis. Description of Technology: Advanced stage cancers are typically marked by metastases of the primary cancer to secondary sites such as lungs, liver, and bones. Such metastatic cancers result in strikingly low 5-year survival rates, underscoring the need for novel therapeutics. For example, bone metastasis of primary breast cancer has a 5-year survival rate of 13%, lung cancer only 1%. There is a need for targeted therapy options specific to metastases. One approach to targeting metastases is to reduce cancer cell migration and invasion. Several mRNAs become localized to subcellular destinations during the metastatic process. These mRNAs may play roles in cell and organelle development – either through corresponding increases in encoded protein concentration or through...
This invention involves ApoA-1 mimetic peptides with multiple amphipathic alpha-helical domains that promote lipid efflux from cells and are useful in the treatment and prevention of dyslipidemic, inflammatory and vascular disorders. IND-enabling studies for one of the peptides, named Fx-5A, are completed in preparation for an IND filing at the FDA, to be followed by a Phase I clinical trial planned for 2017. Disorders amenable to treatment with the peptides include hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, HDL deficiency, hypertriglyceridemia, apoA-I deficiency, acute coronary syndrome, angina pectoris, aortic valve stenosis, atherosclerosis, carotid atherosclerosis, congestive heart failure, cerebral stroke, coronary artery disease, inflammation of the cardiovascular system, intermittent claudication, myocardial infarction, peripheral vascular disease, post-ischemic reperfusion, renal artery stenosis, reperfusion...
This technology includes apoE-apoCII chimeric peptides that possess the ability to lower the triglyceride level both in vitro and in vivo. These peptides can be used for treating hypertriglyceridemia and alleviating other diseases and conditions associated with increased triglycerides. Commercial applications: Treatment for hypertriglyceridemia. Competitive advantages: The peptide sequence is novel and is the first example of an apoC-11 mimetic peptide that contains an additional motif based on ApoE that enhances removal of triglyceride-rich lipoproteins. Source institute: NHLBI. Inventors: Ghosh, Soumitra, Lo, Chih-Hung, Remaley, Alan, Sviridov, Denis.
This technology includes a novel AAV isolate (AAV44.9) to be used as gene therapy for the inner ear for the treatment of deafness. The ability of AAV vectors to transduce dividing and non-dividing cells, establish long-term transgene expression, and the lack of pathogenicity has made them attractive for use in gene therapy applications. Vectors based on new AAV isolates may have different host range and different immunological properties, thus allowing for more efficient transduction in certain cell types. We recently identified a novel AAV isolate as a contaminant of a laboratory stock of adenovirus and is referred to as AAV44.9. Surprisingly, this isolate has high gene transfer activity in a number of cell types including salivary gland cell, liver and nerves. Hearing and balance depend on the function of the inner ear sensory epithelium, which consists of hair cells and a number of supporting cells that provide mechanical support...
Aquaporins, also known as water channels, form pores in cell membranes and selectively transport water in and out of the cell. Aquaporins are involved in regulation of water balance and blood pressure, and thirteen different isoforms have been found in mammals. Aquaporin 2 (AQP2) is located in the collecting duct of the kidney, and is regulated by the peptide hormone vasopressin. AQP2 expression is increased in conditions where there is water retention, such as pregnancy and congestive heart failure, and mutations of AQP2 are associated with nephrogenic diabetes insipidus. Also, lithium treatment, often administered for bipolar disorder, can cause acquired diabetes insipidus by decreasing AQP2 expression. The inventors have developed rabbit polyclonal antibodies directed against a peptide sequence in the C-terminal region of AQP2 (LKGLEPDTDWEEREVRRRQ). The sequence is upstream of phosphorylation sites in this region, and consequently...
Description of Technology: Prostate cancer is the most prevalent form of cancer among all men in the United States (US). It is also the second leading cause of cancer-related deaths in the US among men, largely due to the progressively treatment resistant nature of the disease. Treatment options for early stage prostate cancer include watchful waiting, radical prostatectomy, radiation therapy, and importantly androgen-deprivation therapy (ADT). Prostate cancer is dependent on androgen hormones, such as testosterone, for sustaining and promoting growth. Androgen hormones bind to the Androgen receptor (AR), causing AR localization to the nucleus where a complex is formed that regulates the transcription of critical genes. ADT is accomplished through administering an antagonist to the AR that blocks androgen ligands, or by castration (physical or chemical) to reduce the amount of testosterone. However, the disease frequently advances to...
Niemann-Pick Disease, type C (NPC) is a rare, autosomal recessive, neurodegenerative disease. Approximately 95% of patients with NPC have mutations in NPC1, a gene implicated in intracellular cholesterol trafficking. Mutation of NPC1 causes intracellular accumulation of unesterified cholesterol in late endosomal/lysosomal structures and marked accumulation of glycosphingolipids, especially in neuronal tissue. Thus, NPC patients generally present with hepatosplenomegaly (enlargement of liver and spleen) and neurological degeneration. NPC is highly heterogeneous in both mutations and time of onset. Most mutations in individuals with NPC are unique to the pedigree, are not localized to specific domains and have not been correlated to time of onset or disease severity. Time of onset of the disease varies from neonatal periods to adulthood. We have shown that lysosomal staining in patient derived fibroblasts quantified by FACS analysis is...
Substance use disorder is a chronic medical condition, taking its toll on our public health care and judicial systems in an economically unsustainable way. More than 20 million Americans suffer from substance use disorders. Certainly, the development of prevention and treatment options as alternatives to incarceration is the appropriate and ethical solution to this escalating global problem. Although the recent opioid epidemic has redefined public perception of drug dependence, addiction is not a single illness for which one treatment modality will cure all. Efforts to develop medications to treat this family of disorders must be tailored to the specific substance or substances of abuse, co-morbidities with other neuropsychiatric illnesses, and ultimately individual treatment needs, which significantly increases the challenge. The development of medications to treat cocaine and methamphetamine use disorders has been unsuccessful,...
This CDC developed auscultatory training apparatus includes a database of prerecorded physiological sounds (e.g., lung, bowel, or heart sounds) stored on a computer for playback. Current teaching tools, which utilize previously recorded sounds, suffer from the disadvantage that playback environments cause considerable distortion and errors in sound reproduction. For example, to those trainees using such systems, the reproduced respiratory sounds do not “sound” as if they are being generated by a live patient. Moreover, the aforementioned playback distortions often make it difficult for the listener to hear and interpret the subtleties of a recorded respiratory maneuver. This device includes a software program that allows a user to select prerecorded sounds for playback. The program will also generate an inverse model of the playback system in the form of a digital filter. The inverse model processes a selected sound to cancel the...
Micro-Screen is a CDC developed software program designed to capture images and archive and display a compiled image(s) from a portion of a microscope slide in real time. This program allows for the re-creation of larger images that are constructed from individual microscopic fields captured in up to five focal planes and two magnifications. This program may be especially useful for the creation of data archives for diagnostic and teaching purposes and for tracking histological changes during disease progression. Commercial applications: Medical/cytology training, education and certification. All aspects of applied microscopy/histology, microbial smears, hematology, parasitology, etc.. Clinical diagnostics. Basic and applied biology lab research. Forensic analysis. Competitive advantages: Readily adaptable to other microscopic disciplines. Automated imaging and display provides increased cost efficiency and improves objectivity of...
NeurologyOphthalmologyOncologyInfectious DiseaseImmunologyCardiometabolicInflammationBiologicDiagnostic / BiomarkerAI / ML
Cancer cells can upregulate autophagy – cell destruction – as a response to chemotherapy. Investigators in Dr. Melvin DePamphilis’ laboratory at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) have shown that compounds identified by screening a library of compounds blocks autophagy in some cancer cells (e.g., melanoma) but are not toxic to normal cells. Cancer cells with mutations in the BRAF oncogene are especially dependent on autophagy. Treatment of cancer cells with the BRAF mutation can increase the efficacy of chemotherapy. Proof of concept studies in xenograft mice showed reduction of melanoma tumor size upon treatment with WX8, a lead compound described in the patent application cited below. The technology is available for licensing and/or co-development under a collaborative research agreement. Competitive Advantages: The compounds inhibiting autophagy are selective for cancer cells...
B-cell chronic lymphocytic leukemia (B-CLL) is a cancer characterized by a progressive accumulation of functionally incompetent lymphocytes. Despite high morbidity and mortality, the only available potential cure is allogeneic hematopoietic stem cell transplantation (alloHSCST). However, there is less than a 50% chance of finding a matching bone marrow or blood donor for B-CLL patients. Other clinically tested targeted therapies such as rituximab and alemtuzumab target both malignant and normal B cells, resulting in immunosuppression. Available for licensing are fully human monoclonal antibodies that were selected from the first human post-alloHSCT antibody library. The library was generated from a time point after transplantation at which antibodies to B-CLL cell surface antigens peaked, thus indicating its therapeutic value. Utilizing phage display, the investigators generated a panel of fully human monoclonal antibodies that...
Floxed Bcl-x: Conditional knockout of pro-survival Bcl-x in primordial germ cells was used to study the balance between pro-apoptotic Bax during embryogenesis. Bcl-x is a pro-survival protein that opposes the pro-apoptotic action of Bax which interacts with mitochondria to activate the caspase 9 pathway. Mice in which the Bcl-x gene is inactivated die at E12.5. To be able to study lineage-specific activities of Bcl-x at different stages of development, the Cre-LoxP recombination system was used. Homologous recombination was used to flank the promoter, exon1, and major coding exon2 of the Bcl-x gene with loxP sites. The targeted allele contained a loxP flanked (or floxed) neomycin cassette in the Bcl-x promoter, and an additional loxP site in intron 2. Floxed Bcl-x has been used to study the balance between Bcl-x and Bax in primordial germ cells that undergo controlled levels of cell reduction due to apoptosis, the induction of...
Benzofuranoindoline-containing fungal RiPP-derived compounds and analogs, plus pharmaceutical compositions, and administration methods for treating cancers, including leukemia. Problem: The disclosure targets diseases and disorders where new therapeutic compounds are needed, including cancers such as leukemia. Fungal ribosomally synthesized and post-translationally modified peptides (RiPPs) can show potent bioactivity and structural diversity. Identification of fungal RiPPs has been hindered by limited biosynthetic knowledge and a lack of efficient toolboxes. This limits conversion of fungal genomic potential into characterized developable compound leads. Solution: This disclosure provides compounds of Formula (I) and analogs, and pharmaceutical compositions comprising a disclosed compound and an excipient. Methods are provided for treating or preventing a disease or disorder by administering a pharmaceutically effective amount to a...
CD19 and CD20 are promising targets for the treatment of B-Cell malignancies. Unfortunately, some clinical studies have shown that there is a loss of CD19 or CD20 expression in various cases of lymphomas and leukemias, particularly after treatment with an agent that targets CD19 (e.g., anti-CD19 CAR-T). However, studies have shown that expression of one protein is retained when the other is lost. This suggests that a therapeutic with the ability to simultaneously target both CD19 and CD20 could represent a solution to the drawbacks of current therapies. Researchers at the National Cancer Institute (NCI) have developed the current invention which is an expression construct for a CAR that targets both CD19 and CD20. Specifically, a bicistronic construct has been created for expressing the two CARs from a single vector, thereby allowing for a more efficient transfection of T cells. The result is a more efficient and simultaneous...
Primary liver tumors and secondary hepatic malignancies are among the leading causes of cancer-related deaths. Liver metastases account for 95% of all hepatic cancers, and the liver is the most common site for organ metastasis in the body. The gut microbiome serves an important role in antitumor immunity regulating the efficacy of chemo- and immunotherapies. The liver is exposed to gut bacteria through blood from the intestine, with 70% of the whole liver’s blood supply coming from intestinal blood. Changes in the commensal microbiome may affect immune cell function in the liver. Commensal bacteria have been shown to metabolize primary bile acids to secondary bile acids, and researchers at the National Cancer Institute (NCI) have found that the balance of primary versus secondary bile acids plays a role in liver cancer development. Researchers at the NCI have identified a novel mechanism to enhance anti-tumor immunity in the liver by...
Effective topical wound healing agent that stimulate tissue regeneration through diverse biological activities that correct multiple defects of the wound healing process for the treatment of chronic wounds, such as diabetic foot ulcers (DFUs) and to enhance the rate and quality of healing of acute wounds (burns, injury, surgery).
Treatment for human tuberculosis (TB) and other granulomatous diseases would benefit from high- throughput screening (HTS)-compatible platform replicating physiological conditions in hallmark granuloma lesions. However, currently available screening platforms and 2-D and 3-D cell culture systems lack throughput and key features, and relevant microenvironments present in human TB granulomas, such as the formation of well-organized tuberculoma structure, granuloma lesions, biochemical and physiological gradients, diverse forms, and development of features like enhanced central hypoxia, necrosis, acidosis, and cavity formation. This technology is for bioengineering an HTS-compatible and shelf-stable in vitro tuberculoma bioplatform similar to human tuberculous granuloma lesions for rapid screening of pathogen-targeted and host-directed compounds and other therapeutics against the mycobacterial strains causing TB. This robust 3-D...
The technology focuses on the development of a tetravalent bispecific antibody effective against Bacillus anthracis, the bacterium responsible for anthrax. This antibody combines the specificities of two monoclonal antibodies (mAbs): one targeting anthrax protective antigen (PA) and the other targeting the bacterial capsule. The anti-PA mAb shows potent toxin-neutralizing activity, while the anti-capsule mAb efficiently kills anthrax bacteria. By merging these specificities into a single lgG framework, the resulting bispecific antibody can simultaneously neutralize toxins and kill bacteria, potentially offering comprehensive protection against anthrax infection. The bispecific antibody is produced from transfected mammalian cells, ensuring scalability for large-scale production. This technology represents a significant advancement in anthrax biodefense, providing a simpler, more effective approach for treatment following exposure to...
Chimeric antigen receptors (CARs) combine an antibody-based binding domain (and single chain fragment variable region, scFv) with T cell receptor signaling domains (CD3 zeta with a costimulatory domain, typically CD28 or 41BB). When T cells express CARs, they are activated in a major histocompatibility complex- (MHC) independent manner to kill tumor cells expressing the target to which the scFv binds. CAR T cells targeting the B cell antigen CD19 have resulted in remissions in 60-80% of patients with pre-B cell precursor acute lymphoblastic leukemia (BCP-ALL). However, not all patients respond, and relapses occur in 10% or more of patients who receive anti-CD19 CAR therapy for acute lymphoblastic leukemia (ALL) - primarily due to the loss of the CD19 epitope. Thus, there is a need for advanced therapeutic options to treat those patients who either relapse or are non-responders. To overcome these current limitations, the National...
Glaucoma is one of the world’s leading causes of irreversible blindness. There is no cure and vision lost from glaucoma cannot be restored. Glaucoma is associated with fluid build-up in the eye resulting in an increased intraocular pressure (IOP). The pressure may cause damage to the optic nerve and lead to progressive degeneration of retinal ganglion cells (RGC) and vision loss. Currently, available treatments for glaucoma delay progression by reducing IOP, but no therapies exist to directly protect RGC from degradation and loss. Scientists at the National Eye Institute (NEI) have developed a method to treat glaucoma using exosomes derived from bone marrow-derived mesenchymal stem cells (BMSC). BMSC‐derived exosome administration for glaucoma may confer a significant neuroprotective effect for RGC and prevent vision loss. Isolated exosomes have several immediate advantages for clinical translation compared to potential whole-cell...
Inhibiting the ability of HIV-1, the virus that causes AIDS, to infect cells is one approach to both prevention and treatment of HIV. Scientists at the NIAID Vaccine Research Center have isolated and characterized neutralizing antibodies (VRC01, 02, 03, and 07) that bind to the CD4 binding site of HIV-1 envelope glycoprotein gp120. These human monoclonal antibodies can potentially be used as a therapeutic to: (1) treat an HIV infection, (2) decrease and prevent HIV-transmission from mother to infant, and (3) be effectively combined with anti-retroviral drug therapy. Additionally, the antibodies can be used for detection of HIV-1 infection in biological samples, including body fluids; and tissues from biopsies, autopsies, and pathology specimens. VRC01 has been tested in several phase I clinical trials for safety and pharmacokinetics in infants, adults, and HIV-positive adults. VRC01 is currently being evaluated in a phase II clinical...
In 2023, the World Health Organization (WHO) reported roughly 3 to 5 million cases of severe influenza worldwide, resulting in approximately 290,000 to 650,000 deaths. Given the high disease burden, the needs for both prophylactic and therapeutic influenza strategies remain significant. However, current treatments for influenza are susceptible to resistance and are useful for only a limited post-infection period. The highly conserved epitopes in the stem region of the influenza hemagglutinin (HA) protein are ideal targets for new vaccines, as they elicit broadly neutralizing antibodies. In light of this, researchers at the National Institute of Allergy and Infectious Diseases (NIAID) cloned and expressed HA stem-specific monoclonal antibodies (mAbs) from B cells isolated from human participants in influenza vaccine clinical trials. Four mAbs exhibited particularly potent neutralizing profiles against H1N1 strains, three exhibited very...
Anti-Mullerian inhibiting substance type II receptor (MISRII) specific CAR T cell therapy for the targeted, safe treatment of ovarian cancer. Applications: CAR T therapy for the treatment of ovarian cancer and other gynecologic malignancies Inventors: Daniel Powell, Alba Rodriguez-Garcia.
Chemokine receptors are expressed by many cells, including lymphoid cells, and function to mediate cell trafficking and localization. CC chemokine receptor 5 (CCR5) is a seven-transmembrane, G protein-coupled receptor (GPCR) which regulates trafficking and effector functions of memory/effector T-lymphocytes, macrophages, and immature dendritic cells. Chemokine binding to CCR5 leads to cellular activation through pertussis toxin-sensitive heterotrimeric G proteins as well as G protein-independent signalling pathways. Like many other GPCRs, CCR5 is regulated by agonist-dependent processes which involve G protein coupled receptor kinase (GRK)-dependent phosphorylation, beta-arrestin-mediated desensitization and internalization. Human CCR5 also functions as the main coreceptor for the fusion and entry of many strains of human immunodeficiency virus (HIV-1, HIV-2). HIV-1 transmission almost invariably involves such CCR5-specific variants...
A platform to isolate and expand CD137-positive (CD137 pos ) tumor-infiltrating lymphocytes (TILs) to use in adoptive immunotherapy and translational studies. Problem: Adoptive immunotherapy using either naturally occurring or genetically modified tumor-infiltrating lymphocytes (TILs) is being developed to treat solid tumors clinically. However, methods for isolating and expanding the subset of tumor-reactive TILs for high selectivity and reactivity are yet to be optimized. Solution: The Powell Lab showed that CD137 pos TILs can cause significant reduction in tumor size and higher IFN-λ secretion, indicating that isolation and expansion of CD137 pos + TILs can yield a TIL product of high selectivity and reactivity. Inventors: Daniel Powell.
Summary: The NCI is seeking licensing partners and/or collaborators to perform IND enabling studies to translate the anti-CD206 small molecule into a therapeutic for CD206 expressing cancers. Description of Technology: Pancreatic ductal adenocarcinoma (PDA) accounts for more than 90% of pancreatic cancer cases, and it is one of the most aggressive malignancies with a 5-year survival rate of 6%. The high mortality rate caused by PDA is primarily from the lack of early diagnosis – it is often asymptomatic in early stages – and a poor response to conventional chemotherapy and radiotherapy. One of the major immune cell types present in the PDA microenvironment is a subset of macrophages commonly termed tumor-associated macrophages (TAM). TAMs originate, in part, from circulating monocytes upon activation by CCL2, a chemotactic chemokine secreted and then recruited to the tumor microenvironment by cytokines expressed by PDA cells. TAMs...
Therapeutic development for HIV-1 infection and prevention of transmission Problem: A global pandemic of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) persists, with about 34 million people worldwide currently infected and 2.5 million people newly infected with the virus annually. Inhibition of the initial HIV entry into the host cell has proven elusive to develop therapeutics for HIV-1 infection. Cellular infection by HIV-1 begins when the viral envelope glycoprotein gp120 binds to the T-cell receptor protein CD4 anchored to the cell membrane. This binding event induces a conformational change that exposes the binding site for the transmembrane chemokine co-receptor (CCR5 or CXCRC4), and the rearranged protein helix bundle inserts into the host cell membrane for viral entry. Solution: In a cross-university collaboration, researchers have utilized structure-based drug design and synthesized dual...
Mosquitoes are responsible for spreading many viruses that can make people sick, including dengue, Zika, chikungunya, yellow fever, and more. The Centers for Disease Control and Prevention's (CDC's) new autocidal gravid ovitrap (AGO) mosquito trap is an inexpensive, simple-to-assemble, and easy-to-maintain trap that targets female mosquitoes looking for a place to lay eggs. The current trap model stands 18 inches (45cm) tall and is made of a 5-gallon (18L) bucket. The AGO trap's unique design lures mosquitoes by using water and an all-natural, organic hay attractant. Once inside, female mosquitoes are captured on a nontoxic, sticky glue adhesive placed inside the capture chamber. The AGO trap has been successfully used by mosquito control programs for mosquito surveillance and control. Field trials in which the AGO trap has been installed in most homes in a community have shown it not only reduces mosquito populations but also rates...
Clinically known as Neuronal Ceroid-Lipofuscinoses (NCL), Batten disease, is a rare neuron killing disease and one of the lysosomal storage disorders (LSDs). It is associated with a mutation or lack of palmitoyl-protein thioesterase-1 (PPT1) gene. It manifests very early in a child's life causing absence of brain activity as early as 4 years of age. Dr. Mukherje of NICHD has discovered and developed N-t-BuHA, a chemical derivative of hydroxylamine that mimics the action of PPT1 enzyme. Compared to hydroxylamine, N-t-BuHA has been shown to be non-toxic in mice expressing batten disease. In addition, NtBuHA exhibited potent antioxidant property and extended the life of the diseased mice. NtBuHA has shown promising therapeutic potential to treat NCL-LSDs. Competitive Advantages: First of its kind to treat INCL and other LSD. Non-toxic dertivative therapeutic against thioesterase deficiency disorders. Commercial Applications: Small...
This invention includes human induced pluripotent stem cell (iPSC) lines that harbor a single copy dCas9-BFP-KRAB at the CLYBL safe harbor locus (mediating CRISPR inhibition of human gene expression) and/or a single copy of dox-inducible NGN2 at the AAVS1 locus (enabling the differentiation of the iPSCs into neurons). The CRISPR-mediated inhibition of human gene expression is maintained into the differentiated neurons, permitting functional studies of targeted genes in neurons. Commercial applications: The stem cell lines can be used for forward genetic and chemogenetic screens for drug tests of neurological diseases. Competitive advantages: The stem cell lines included in this technology permit direct genetic and screening approaches on neurons. Source institute: NINDS. Inventors: Kampmann, Martin, Ludwig, Connor, Tian, Ruilin, Ward, Michael.
A plasmid encodes human interleukin-8 (IL-8) receptor CXCR1. IL-8 is a chemo-attractant cytokine that attracts and activates neutrophils in inflammatory regions. Commercial applications: A research material that can be used in the development of assays, validation of products or in quality control.. Competitive advantages: Speed up product development with NIH developed material that has already been tested and validated.. Source institute: NIAID. Inventors: Ahuja, Sunil, Murphy, Philip.
Methods of enhancing engraftment of donor hematopoietic stem cells (HSCs) by reducing expression or activity of CXCR4 in HSCs is described. HSC are the only cells in the bone marrow that are both pluripotent and long lived. Bone marrow transplantation (BMT) using HSC is an increasingly common medical therapy for severe hematologic cancers and primary hematologic immunodeficiencies. However, for significant HSC engraftment to occur there must usually be pre-transplant conditioning with either irradiation or chemotherapy or both. The technology described herein shows that it is possible to replace HSC without the need for pre-transplant conditioning regimen. It is known that the chemokine receptor CXCR4 plays a critical role in HSC homing to the bone marrow and in HSC quiescence. The inventors have identified a patient in which one copy of CXCR4 had been deleted in a somatic mutation of an HSC and this cell had clonally repopulated the...
Summary: The NCI seeks research co-development partners and/or licensees to further develop this nanobody as a possible treatment of COVID-19 infections. Description of Technology: Since its emergence in 2019, COVID-19 infected over 600 million people and over 6 million people have died from the disease. COVID-19 is an infectious disease caused by the SARS-CoV-2 virus. Neutralizing antibodies have been developed to bind to the receptor binding domain (RBD) on the spike (S) protein. Blocking the interaction of the RBD and the ACE2 receptor, is critical in neutralizing the virus. However, the S2 subunit, is also critical for viral infection and entry into human cells. The S2 subunit is highly conserved across many coronaviruses, however, there are currently no effective antibodies targeting this S2 subunit. The inventors isolated the J1B4 camel VHH nanobody, a potent S2 binder that can neutralize all the known variants of SARS-CoV-2,...
The treatment of cancer using immunotherapies has garnered substantial attention and excitement considering the clinical benefits observed in patient populations previously refractory to treatment. Tumor infiltrating T cells can significantly impact cancer progression and immunotherapy response; however, immunosuppressive tumor microenvironments can impede antitumor T cell induction, trafficking, and local activity. Thus, personalized immunotherapy approaches have shown limited efficacy against most solid tumors. In addition, manufacturing complexities remain, with high costs of development and implementation. Novel approaches are needed to effectively induce antitumor T cell responses despite heterogeneity in the tumor microenvironment and antigen landscape. Improved development costs and strategies for these approaches are also desired. Researchers at the NCI developed a method to harness heterogenous antigens for the effective...
One major challenge in the development of effective cancer therapies is a lack of universal, cancer specific markers in target cells. The current standard therapies rely on surgery, chemotherapy, and radiation therapy. Such procedures lead to a population of resistant cancer cells that makes further applications of chemotherapy/radiation therapy ineffective. Additionally, the systemic application of chemotherapy lacks specificity and has off-target systemic effects that lead to adverse side effects. A considerable effort has been devoted to identifying and targeting specific extracellular cancer markers using antibody based therapies. However, diminished access to new cancer cell surface markers has limited the development of corresponding antibodies. Investigators at the National Cancer Institute have discovered a novel method that employs presentation of intracellular cancer antigens on the cell surface to convert the tumor into...
The National Cancer Institute's Molecular Targets Development Program is seeking parties interested in collaborative research to further develop, evaluate, or commercialize cancer inhibitors isolated from the African plant Phyllanthus englerii. The technology is also available for exclusive or non-exclusive licensing. This invention involves compounds extracted from the African plant Phyllanthus englerii that have potential cancer-inhibiting activity. Bioassay-guided fractionation of the purified extracts revealed a series of novel chemical entities which are named Englerin A-F. The englerins and their derivatives are useful in the treatment of a number of cancers, particularly renal cancer. The englerins exhibit selective and potent renal cell inhibitory activity in vitro. These compounds can be recovered in reasonable yield from natural product extracts and are well suited for synthetic chemistry derivativization. A sufficient...
The National Cancer Institute, Cancer and Inflammation Program seeks parties interested in collaborative research to further co-develop inhibitors of STAT proteins for the treatment of cancer. Signal transducer and activator transcription (STAT) proteins, specifically STAT1, 2, 3, 4, 5a, 5b, and 6, are involved in the cellular and biological processes of cell proliferation, differentiation, apoptosis, host defense, and transformation. Constitutively active STAT proteins occur in many human tumor cells and cells transformed by oncoproteins. Inhibiting these STAT proteins has great therapeutic potential in the treatment of certain cancers and a common approach to inhibition of these proteins involves targeting the kinases that activate STAT. This method typically leads to non-selective inhibitors and is associated with off-target related toxicity. NCI scientists discovered a family of short peptides that bind to the N-terminal domains...
Hypoxia is a characteristic of many solid tumors resulting from accelerated cellular proliferation and inadequate vascularization. HIF-1 is a transcription factor critical for maintaining cellular homeostasis in, and adaptively responding to, low oxygen environments. HIF-1 becomes activated through binding to the transcriptional co-activator protein p300. Disruption of the HIF-1/p300 interaction could potentially modulate HIF-1 activity. Researchers at the National Cancer Institute (NCI) have developed small molecule compounds that inhibit the activity of HIF-1. The HIF-1 inhibitor compounds are designed around the scaffold of naturally occurring metabolite eudistidine. Compounds eudistidine A and C have been shown to disrupt the HIF-1/p300 interaction in vitro. Eudistidine C has also inhibited growth of malaria at low micromolar concentrations. Competitive Advantages: Lack of general cytotoxic effects. Novel molecular scaffolds and...
Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual''s innate and adaptive immune system to fight against specific diseases, including cancer with fewer side-effects and more specific anti-tumor activity in individual patients. T cell receptors (TCRs) and Chimeric Antigen Receptors (CARs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response to destroy abnormal cells. When a TCR/CAR is stimulated by an antigen, signaling pathways activated in the T cell lead to the production of proteins such as cytokines, which mediate the immune response and ultimately lead to the death of the diseased target cell. Scientists at the National Cancer Institute (NCI) Surgery Branch have developed T cells genetically engineered to express the human interleukin 12 (IL-12) cytokine only in the tumor environment. Thus, IL-12 is...
Natural killer T cells (NKT) are a unique lymphocyte population that has T-cell and NK cell functional properties in order to rapidly elicit an immune response. alpha-galactosylceramide (alpha-GalCer) is a potent NKT stimulator and induces of IFN-gamma release to promote immunity against tumors and infectious agents. Humans have natural antibodies against alpha-galactose, which may be one of the reasons why the human clinical trials of alpha-GalCer or KRN7000 were not very successful. Beta-ManCer is a new class of NKT agonist that induces immune responses alone, through nitric oxide and TNF-alpha-dependent mechanisms, or synergistically with alpha-GalCer to enhance alpha-GalCer''s efficacy. Since beta-ManCer does not have alpha-galactose, which can be neutralized by natural antibodies, patients could be treated with multiple doses without negative side effects associated with the loss of IFN-gamma production. Hence, beta-ManCer is a...
The National Cancer Institute, Nanobiology Program seeks parties interested in collaborative research to co-develop engineered molecules therapies. Efforts to engineer antibody-based therapeutics, to date, have encountered technical limitations due to the relatively large fragment size and short fragment half-life. Antibody fragments are emerging as promising biopharmaceuticals because of their relatively small size and other unique properties. However, compared with full-size antibodies, these antibody fragments lack the ability to bind to some Fc receptor and have reduced half-lives. NCI scientists have developed small (∼27 kDa) antibody fragments that are potentially useful for therapeutic development. These are monomeric IgG fragment (mFc) compositions; they have long half-lives, are functional (pH dependent binders of neonatal Fc receptor - FcRn); soluble, and they express in E. coli efficiently. The molecules may serve as a...
Adoptive cell therapy (ACT) using genetically engineered T-cell receptors (TCRs) is a promising cancer treatment. These TCRs target genetic mutations unique to patients and play an important role in tumor regression. However, mutation-reactive T-cells and their TCRs can be difficult to identify and isolate from patients. Therefore, we need more efficient methods of isolating mutation-reactive T-cells for use with ACT. Researchers at the National Cancer Institute (NCI) have developed a novel method of isolating mutation-reactive T-cells from a patient’s peripheral blood lymphocytes (PBL). The researchers found that mutation-reactive T-cells in the PBL are enriched with various markers including CD8, programmed cell death 1 (PD-1), and T cell immunoglobulin and mucin domain 3 (TIM-3). These T-cells and their TCRs can be isolated from the blood and then administered to patients as a cancer therapeutic. The National Cancer Institute,...
There is evidence that the metabolic effects of endocannabinoids are mediated by CB1 receptors in peripheral tissues. While prior attempts at generating CB1 receptor blockers have had serious neuropsychiatric side effects, inventors at NIH have discovered compounds that block CB1 receptors with reduced brain penetrance. In addition, some of these compounds also have a direct inhibitory effect on inducible nitric oxide synthase (iNOS), whereas another group of the compounds directly activates AMP kinas. These dual-target compounds may be useful for treating metabolic disease and related conditions such as obesity and diabetes and their complications, including liver or kidney fibrosis, without the dangerous the side effects. Commercial applications: Treatment of metabolic disease and related conditions such as diabetes, obesity and fibrotic disease.. Competitive advantages: Cannabinoid receptor blockers with reduced brain penetrance...
The invention concerns novel capsid-free AAV vectors that can be used for gene delivery and gene therapy applications. The invention provides for a linear nucleic acid molecule comprising in this order: a first adeno-associated virus (AAV) inverted terminal repeat (ITR), a nucleotide sequence of interest, and a second AAV ITR, wherein said nucleic acid molecule is devoid of AAV capsid protein coding sequences. The said nucleic acid molecule can be applied to a host at repetition without eliciting an immune response. Methods of producing and purifying this nucleic acid molecule, as well as its use for gene transfer and gene therapy are also described. Commercial applications: The commercial applications of the technology relate to the field of gene therapy. It may offer significant advantages compared to existing methods of gene delivery and gene therapy.. Competitive advantages: The AAV vectors described in the invention devoid the...
This technology includes efficient lentiviral gene delivery system for both guide RNA and Cas9 endonuclease as a method to cure sickle cell disease. Gene correction is an ideal gene therapy strategy for hereditary disease, including sickle cell disease. To deliver both guide RNA and Cas9 endonuclease into target cells, we used HIV-l based lentiviral vector system, which allows for efficient gene delivery in various cells, including hematopoietic stem cells and ES/1PS cells in this system, transgene expression cassettes can be integrated into genomic DNA in target cells, which results in long‐ term transgene expression. Out data demonstrate that Cas9/CypA fusion proteins can be delivered with lentiviral particles, and the Cas9 fusion proteins have an endonuclease function to induce GFP DNA double strand break. Commercial applications: Perform gene correction in the β-globin gene and/or BCL11lA gene knock-down in hematopoietic stem...
Novel and potent caspase 1 inhibitors are available for licensing. In particular, this technology discloses potent and selective caspase 1 inhibitors that target the active site of the enzyme. Caspase 1 is known to play a pro-inflammatory role in numerous autoimmune and inflammatory diseases and therefore represents an excellent target for treatment of a broad range of diseases, including but not limited to Huntington's, amyotrophic lateral sclerosis, ischemia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and sepsis. Not surprisingly this enormous potential has resulted in at least three caspase 1 inhibitors entering clinical trials (VX-740, IDN-6556, and VX-765) in recent years. Commercial applications: Potential therapeutic for a broad range of autoimmune diseases. Potential therapeutic for a broad range of inflammatory diseases. Source institute: NCATS. Inventors: Boxer, Matthew, Thomas, Craig.
Antibacterial and anti-inflammatory activity of a cationic disubstituted dexamethasone-spermine conjugate Applications: Antibacterial development Anti-inflammatory agent Inventors: Scott Diamond, Paul Janmey.
The invention hereby offered for licensing is in the field of Immunotherapy and more specifically in therapy of autoimmune diseases such as Type I diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosis and immune mediated allergies such as asthma as well as in transplantation-related disorders, such as graft acceptance and graft-versus-host-disease (GVHD). While the role of FOXP3 + regulatory T cells (Tregs) in the maintenance of self-tolerance and immune homeostasis has been established and thus their use in adoptive immunotherapy has been contemplated, there is still no good way to purify and expand these cells in an efficient and reproducible manner ex vivo for use in human therapy. The subject invention provides a method that allows such purification for use in expansion cultures to generate sufficient numbers of cells and purity for cell-base immunotherapy. The method is based on the finding that...
T cell immunotherapy is used in the treatment of various pathologies – including cancers and infections. Current therapies employ chimeric antigen receptors (CARs) consisting of the intracellular fragment of CD3-zeta as the signaling domain with varied combinations of co-stimulatory, transmembrane, spacer/hinge, and extracellular targeting domains. While effective in treating hematological malignancies, CAR T cells need to be activated through T cell receptor (TCR) activation. Such activation is subject to various regulatory and inhibitory mechanisms that can limit their full therapeutic potential. Moreover, CAR T cells are less effective in the treatment of solid tumors due to exhaustion. There remains a need for effective immunotherapies to treat solid tumors as well as hematological malignancies. Researchers at the National Cancer Institute (NCI) have found that after T cell receptor (TCR) activation, the linker for activation of T...
The chemokine receptor, CCR4 is a seven transmembrane G protein-coupled cell surface receptor molecule with selective expression on cells of the hematopoietic system. In adult T cell leukemia (ATL), the cell-surface expression of CCR4 on leukemic cells has been found to be nearly universal. Therefore, a CCR4-directed chimeric antigen receptor (CAR) -cell may provide an effective therapeutic against ATL. Researchers at the National Cancer Institute (NCI), Lymphoid Malignancies Branch, developed a lentivirus-derived CAR against the CCR4 molecule. The CAR can be directed to either genetically modified autologous or to allogeneic T or natural killer (NK) -cells to develop the ATL therapy. This technology includes a method of identifying lymphoid or solid tumors that produce CCR4 mRNA and then utilizing CD3+ T cells and/or NK cells to generate genetically modified T cells and/or NK cells (autologous or allogeneic) that express the CCR4...
Description of Technology: Mesothelin (MSLN) is an excellent target for antibody-based therapies of cancer because of its high expression in many malignancies but lack of expression on essential normal tissues. Unfortunately, a large fragment of MSLN is shed from cancer cells, causing the currently available anti-MSLN antibodies (and immunoconjugates thereof) which bind to the shed portion of MSLN to quickly lose their therapeutic effectiveness over time. Indeed, the shed portion of MSLN can act as a decoy for these antibodies, further limiting them from reaching and destroying tumor cells. Scientists at NCI previously developed MAB15B6, an antibody that specifically binds to the unshed region of MSLN and blocks MSLN shedding. Building on this discovery, the inventors made specific modifications to CARs which utilize humanized MAB15B6. T cells expressing these enhanced CARs are very active in blocking tumor progression in xenograph...
Chimeric antigen receptors (CARs) are hybrid proteins that consist of two major components: a targeting domain and a signaling domain. The targeting domain allows T cells which express the CAR to selectively recognize and bind to diseased cells that express a particular protein. Once the diseased cell is bound by the targeting domain of the CAR, the signaling domain of the CAR activates the T cell, thereby allowing it to kill the diseased cell. This is a promising new therapeutic approach known as adoptive cell therapy (ACT). Researchers at the NCI Experimental Transplantation and Immunology Branch developed a CAR that recognizes human tumor necrosis factor receptor superfamily member 8 (TNFRSF8, also known as CD30). The expression of CD30 is deregulated in a variety of human cancers, including many lymphomas. By creating a CAR that recognizes CD30, it may be possible to treat these cancers using adoptive cell therapy. Competitive...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for a set of Chimeric Antigen Receptors (CARs) that target the γδ T-Cell Receptor. Description of Technology: T cells express two main types of receptors based on the proteins that make up the T-cell receptor (TCR) heterodimers: ab (alpha beta) and gd (gamma delta). T cells expressing the gd TCR are detected at lower frequencies compared with T cells expressing the ab TCR. gd T cells make up 0.3-10% of peripheral blood T cells. The gd TCR is expressed on the cell surface of several aggressive cancers, including – but not limited to – hepatosplenic T-cell lymphoma, primary cutaneous gd T-cell lymphoma and T-cell acute lymphoblastic leukemia (T-ALL). These cancers carry poor prognosis as they are often resistant to chemotherapy. In addition, to their roles in cancer development, gd T cells may also play role in autoimmune diseases,...
Chimeric antigen receptors (CARs) with high affinity for mesothelin that can be used as an immunotherapy to treat cancers that express mesothelin, such as pancreatic cancer, ovarian cancer, and mesothelioma. The technology includes CAR constructs with one of three different mesothelin-specific antibody portions, including either the mouse-derived SS or SS1 antibody fragments or the human HN1 antibody fragment. Mesothelin is a protein cancer antigen with limited expression on normal cells that is overexpressed by cancer cells. CARs are hybrid proteins consisting of an antibody portion that recognizes a cancer antigen, such as a mesothelin-specific antibody, fused to receptor signaling domains that serve to activate the CAR-expressing cell to kill tumor cells. Cells that express CARs, most notably T cells, are highly reactive against their specific tumor antigen in an MHC-unrestricted manner to generate an immune response that promotes...
Description of Technology: Chimeric antigen receptors (CARs) are hybrid proteins consisting of an antibody binding fragment fused to protein signaling domains that cause T-cells which express the CAR to become cytotoxic. Once activated, these cytotoxic T-cells can selectively eliminate the cells which they recognize via the antibody binding fragment of the CAR. Thus, by engineering a T-cell to express a CAR that is specific for a certain cell surface protein, it is possible to selectively target those cells for destruction. This promising new therapeutic approach is known as adoptive cell therapy. CD22 is a cell surface protein expressed on a large number of B-cell lineage hematological cancers, such as leukemia and lymphoma. Several promising therapies are being developed which target CD22, including therapeutic antibodies and immunotoxins. This technology concerns the use of a high affinity antibody binding fragment to CD22 (known...
Chimeric antigen receptors (CARs) are hybrid proteins consisting of an antibody binding fragment fused to protein signaling domains that cause T-cells which express the CAR to become cytotoxic. Once activated, these cytotoxic T-cells can selectively eliminate the cells which they recognize via the antibody binding fragment of the CAR. By engineering a T-cell to express a CAR that is specific for a certain cell surface protein, it is possible to selectively target those cells for destruction. This is a promising new therapeutic approach known as adoptive cell therapy. CD276 (a.k.a., B7-H3) is a tumor-associated antigen that is expressed on the cell surface of several cancers, including neuroblastomas, prostate cancer, ovarian cancer and some lung cancers. This technology concerns the development of CARs comprising an antigen-binding fragment derived from the MGA271 antibody. The resulting CARs can be used in adoptive cell therapy...
Zika virus (ZIKV) can be passed from a pregnant woman to her fetus. Infection during pregnancy can cause microcephaly and other severe birth defects. Currently, there are no vaccines to prevent or medications to treat Zika infections. CDC engineered chimeric Zika viruses on the dengue virus (DENV) sub-type 2 (D2) PDK-53 vaccine backbone (D2 PDK-53) for potential development of a live-attenuated Zika vaccine. These chimeric viruses could also be used for other research purposes such as development of diagnostic tests. The cDNA genetic clones for the chimeric constructs have been successfully engineered, and scientists in the laboratory are in the process of deriving infectious chimeric D2 PDK-53/Zika viruses. Commercial applications: Zika vaccine development or combined vaccination strategies using both live-attenuated and inactivated ZIKV vaccine (West Nile/ZKV) candidates. Combination vaccine with other flaviviruses such as dengue or...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for Chimeric VLP Vaccines to Prevent HTLV-1 Infection. Description of Technology: There is currently no approved vaccine to prevent human T-cell leukemia virus type I (HTLV-1) infection, a highly oncogenic virus linked to serious diseases like adult T-cell leukemia/lymphoma (ATLL) and Tropical Spastic paraparesis /HTLV-1-Associated Myelopathy (HAM/TSP). Existing interventions are limited to behavioral prevention, leaving millions at risk, especially in underserved global regions. A safe and effective vaccine is urgently needed to fill this critical public health gap. This invention is a nucleic acid-based vaccine that generates virus-like particles (VLPs) in the body using HTLV-1 Env and gag proteins to trigger a protective immune response against HTLV-1 infection. With no approved vaccines available and millions at risk—particularly...
The technology provides the isolation of a functional DNA sequence comprising a chromatin insulating element from a vertebrate system and provides the first employment of the pure insulator element as a functional insulator in mammalian cells. The technology further relates to a method for insulating the expression of a gene from the activity of cis-acting regulatory sequences in eukaryotic chromatin. This technology could be of major importance in providing a mechanism and a tool to restrict the action of cis-acting regulatory elements on genes whose activities or encoded products are needed or desired to be expressed in mammalian transgenic systems. This technology provides the first pure insulator element to function solely as an insulator element in human cells. Accordingly, this technology could have tremendous practical implications for transgenic technology and human gene therapies, either in vitro or in vivo. The technology...
This technology includes Spodoptera frugiperda (Sf9) cells which were developed to produce recombinant adeno-associated virus. The cells maintain a copy of the vector genome and for production, require infection with a single baculovirus that expresses either structural and nonstructural proteins to produce rAAV, or the non-structural (Rep) proteins to produce ceDNA. Commercial applications: Spodoptera frugiperda (Sf9) cells were developed to produce recombinant adeno-associated virus. This technology can be used for the large-scale production of recombinant adeno-associated virus (rAAV), a critical component in gene therapy, by employing Spodoptera frugiperda (Sf9) cells for efficient and controlled replication and packaging of the virus. Competitive advantages: The simplified process has manufacturing advantages compared to the co-infection systems (using either 2 or 3 baculoviruses), with higher production and improved yields....
The current invention provides nucleic acid sequences comprising the genomes of infectious hepatitis C viruses (HCV) of genotype 1a and 1b. It covers the use of these sequences, and polypeptides encoded by all or part of the sequences, in the development of vaccines and diagnostic assays for HCV and the development of screening assays for the identification of antiviral agents for HCV. Additional information can be found in: Yanagi et al., "Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee," Proc. Natl. Acad. Sci. USA (1997 August) 94(16):8738-8743; and Yanagi et al., "Transcripts of a chimeric cDNA clone of hepatitis C virus genotype 1b are infectious in vivo," Virology (25 April 1998) 244(1):161-172. Source institute: NIAID. Inventors: Yanagi, Masayuki, Bukh, Jens, Emerson, Suzanne, Purcell, Robert.
Currently, adeno-associated virus (AAV) represents the gene therapy vehicle of choice because it has many advantages over current strategies for therapeutic gene insertion. AAV is less pathogenic than other virus types; stably integrates into dividing and non-dividing cells; integrates at a consistent site in the host genome; and shows good specificity towards various cell types for targeted gene delivery. To date, 11 AAV isolates have been isolated and characterized. New serotypes derived from non-human animal species have added to the specificity and repertoire of current AAV gene therapy techniques by avoiding the immunologic complications associated with human isolates. This invention describes vectors derived from an avian AAV. These vectors have innate properties related to their origin that may confer them with a unique cellular specificity in targeted human gene therapy and a unique immunologic profile that would avoid...
Nanocluster agents that enable imaging through cyanine dyes and/or photosensitizers without the need for additional carrier molecules. Problem: There is a need for visual inspection and feedback before and during surgery for removing tumors and cancerous cells from surrounding healthy tissue. Better visualization can lead to better prognosis because more of the tumor will be removed during surgery. Solution: The inventors have developed nanoclusters that are stable and detectable on MRI, fluorescence, and photoacoustic imaging. These nanoclusters, containing three or more metallic nanoparticles, are stable under physiologic conditions and can be taken up by tumors for strong visualization before and during surgery. Inventors: Ahmad Amirshaghaghi, Zhiliang Cheng, Jayesh Thawani, Andrew Tsourkas.
Innovative, efficacious, and novel treatment strategy for overcoming resistance to BH3 mimetics in Acute Myeloid Leukemia (AML) and myelodysplastic syndrome (MDS)
Problem: Materials used for bone transplants, and as scaffolds for tissue restoration, need particular features to work well. Current materials have shortcomings that complicate treatment. - Dried silica gels are very attractive because of their nanometer-sized pores, but they lack larger pores that exist in natural bone. - Composite materials... Problem: Materials used for bone transplants, and as scaffolds for tissue restoration, need particular features to work well. Current materials have shortcomings that complicate treatment. - Dried silica gels are very attractive because of their nanometer-sized pores, but they lack larger pores that exist in natural bone. - Composite materials may have larger pores, but the fibers are usually dense ceramics which are less biocompatible. There is a need for materials that combine the high surface area of dried gels with the larger pores of fibrous composites. Solution: Researchers at the...
Co-expression of modified chimeric antigen receptor (CAR) T cells and cholesterol 25-hydroxylase (CH25H) in a single construct for treatment of solid tumor and hematological cancers. Problem: CAR T cell therapy is a treatment in which T cells collected from a patient are engineered to produce CARs that recognize and attack cancer cells. While it is efficacious at treating some patients with hematologic malignancies, many patients relapse and there is little success at treating solid tumors, which represent ~90% of adult cancers and 40% of childhood cancers. Cancer cells can evade CAR T therapy through trogocytosis, whereby an antigen on cancer cells is transferred to cytotoxic T lymphocytes (CTLs). This causes CTLs to become exhausted, be mistakenly recognized as targets and killed, and allows cancer cells to survive. Partial loss of CH25H in intratumoral T cells leads to increased trogocytosis and suppresses the viability and...
Summary: The National Cancer Institute (NCI) is seeking research co-development partners and/or licensees for NCI’s compositions and methods to enhance the efficacy of dendritic cell (DC)-based cancer vaccines. Description of Technology: Current dendritic cell (DC)-based cancer vaccines are limited by impaired DC function due to cancer-driven lipid imbalances and other immunosuppressive factors reducing vaccine effectiveness. To address this issue, NCI has generated dendritic cells in the presence of omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) and their derivatives, or specialized pro-resolving lipid mediators, to restore and enhance the dendritic cells’ antigen-presenting function and anti-tumor efficacy. This approach could significantly improve the potency of DC-based cancer vaccines, offering a promising strategy to overcome a major limitation in current cancer immunotherapies. NCI is actively...
This technology includes a vaccine for lowering plasma triglycerides by inducing the formation of autoantibodies against either ANGPTL3 or ANGPTL4, which are inhibitors of Lipoprotein Lipase. This was done by conjugating synthetic peptides based on ANGPTL3 or ANGPTL4 to virus- like particles (VLPS). Injection of the vaccine in animal models was shown to induce the autoantibody against the target and to lower plasma triglycerides. Commercial applications: Development into a novel therapy for lowering plasma triglycerides. Competitive advantages: The vaccine strategy for lowering plasma triglycerides is novel and could represent a low-cost alternative to drug therapy. Source institute: NHLBI. Inventors: Fowler, Alexandra, Remaley, Alan, Amar, Marcelo, Chackerian, Bryce.
Malaria is the single leading cause of death, especially among children, in the developing world. Malaria is caused by infection with parasites of the genus Plasmodium , transmitted by mosquitos. In addition to transmission, vital steps in the parasite lifecycle occur in the mosquito host. The invention offered for licensing relates to therapeutic compounds and related pharmaceutical compositions that can be used in the prevention and treatment of malaria infection. More specifically, the invention is drawn to compounds that may kill sexual and mosquito stage malaria parasites to block transmission. Specifically claimed is the antihistamine Ketotifen, which has demonstrated activity blocking parasite development in mosquitoes. Also claimed are treatments encompassing Ketotifen with other existing antimalarial drugs in a combination treatment aimed at multiple stages in the malaria life cycle. Commercial applications: Prevention and...
Technology Overview: Scars are a natural part of the healing process, and there is currently no good treatment for preventing scar formation. Researchers at the University of Pennsylvania have discovered that topical application of a class of compounds promotes wound healing and inhibits scar formation. The compound studied in their preclinical wound... Inventors: George Cotsarelis.
This invention pertains to a CDC developed sonic aerosol generator that provides a controllable, stable concentration of particulate aerosol over a long period of time for aerosol exposure studies. Specifically, in situ testing data indicate uniform aerosol stability can be maintainable for greater than 30 hours at concentrations of 15 mg/m 3 or more. Additionally, the technology was specifically developed for, and validated in, animal studies assessing exposure to airborne multi-walled carbon nanotubes (MWCNT). It has been suggested that workers may be at risk for exposure to nanosized particles during the manufacture, handling, and cleanup of engineered nanomaterials. Compared to other technologies, this CDC aerosol generator is particularly helpful when used for generating high testing concentrations of MWCNT aerosols that more accurately represent particulate levels that may be seen in a workplace environment. Commercial...
Podocytes, cells of the visceral epithelium in the kidneys, are a key component of the glomerular filtration barrier. Podocyte damage and loss contribute to the initiation of glomerular diseases. NIH investigators recently established long-term urinary cell cultures from two patients with focal segmental glomerulosclerosis and two healthy volunteers, via transformation with the thermosensitive SV40 large T antigen (U19tsA58) together with human telomerase (hTERT). Characterization of randomly selected clonal cell lines from each human subject showed mRNA expression for the podocyte markers synaptopodin, nestin, and CD2AP in all clones. Podocin mRNA was absent from all clones. The expression of nephrin, Wilms tumor 1 (WT1), and podocalyxin mRNA varied among the clones, which may be due to transformation and/or cloning. These novel human urine-derived podocyte-like epithelial cell lines (HUPECs) generated from urine of patients and...
The National Institutes of Health announces the generation of a construct by ligating 2.5kb human podocin promoter sequence to gene encoding reverse tetracycline-controlled transcriptional activator which enables tetracycline-inducible podocyte specific gene of interest expression with another construct consisting of tetracycline responsive element, minimal CMV promoter and gene of interest. Podocytes are post-mitotic epithelial cells that are positioned on the exterior aspect of the glomerular capillary wall and contribute to the selective molecular permeability of glomeruli. Podocyte damage or dysfunction results in loss of the characteristic foot processes that normally interdigitate and form the selective permeability barriers composed of filtration slits bridged by slit diaphragms. Minimal damage causes proteinuria that in the case of minimal change disease can be reversed by steroid treatment. In focal segmental...
The noroviruses (known as "Norwalk-like viruses") are associated with an estimated 23,000,000 cases of acute gastroenteritis in the United States each year. Norovirus illness often occurs in outbreaks, affecting large numbers of individuals, illustrated recently by well-publicized reports of gastroenteritis outbreaks on several recreational cruise ships and in settings such as hospitals and schools. Norovirus disease is clearly important in terms of medical costs and missed workdays, and accumulating data support its emerging recognition as important agents of diarrhea-related morbidity. Because the noroviruses cannot be propagated by any means in the laboratory, an important strategy in their study is the development of molecular biology-based tools. This invention reports the development of recombinant baculoviruses carrying the capsid gene from several caliciviruses associated with human disease. Growth of these baculovirus...
Porcine enteric calicivirus (PEC) is a member of the genus Sapovirus in the family Caliciviridae. This virus causes diarrheal illness in pigs, and is presently the only enteric calicivirus that can be grown in cell culture. In addition to its relevance to veterinary medicine as a diarrheal agent in pigs, PEC serves as an important model for the study of enteric caliciviruses that cause diarrhea and that cannot be grown in cell culture (including the noroviruses represented by Norwalk virus). The development of an infectious cDNA clone is important because it enables the use of “reverse genetics” to engineer mutations of interest into the genome of PEC and to study their effects. In addition, it allows the introduction of foreign coding sequences into the genome of PEC that could be useful for vaccine development in swine and possibly humans. This discovery has both basic research applications such as mapping mutations involved in...
CDC researchers have developed methods of producing unlimited quantities of Group-C (GpC) rotavirus antigens. GpC rotaviruses are a major, worldwide cause of acute gastroenteritis in children and adults that is distinct from Group-A rotavirus. However, GpC rotaviruses cannot be grown in culture, resulting in a lack of tools for detection and treatment of GpC rotavirus disease. Consequently, the true clinical burden of GpC rotavirus disease has not been clearly established. This technology allows for the expression of the three major capsid proteins (VP2, VP6 and VP7) of GpC rotavirus by recombinant baculovirus and assembly of virus-like particles (2-6-7 and/or 6-7) within insect cells. Further, this CDC generated technology allows for the large-scale access to GpC rotavirus antigens, previously infeasible, and will permit use of these novel virus-like particles for the development of rotavirus diagnostic assays and improved vaccine...
Summary: Researchers at UCI and NCI seek licensing to adopt new applications for a family of far-red to near-infrared emission coumarin-based luciferins (CouLuc) with complementary mutant enzymes. Description of Technology: Bioluminescence imaging with luciferin-luciferase pairs is a well-established technique for tracking cells and other biological features in animal models. Bioluminescent is a chemical process which does not require an external input for excitation. Bioluminescent imaging is often limited to monitoring single processes in vivo due to the lack of distinguishable probes. Additionally, existing probes typically operate with light in the visible range, which is highly scattered and exhibits poor tissue penetration. To address these issues, researchers at UCI and NCI synthesized a new family of coumarin-based luciferins (CouLuc) with complementary mutant enzymes that exhibit far-red to near-infrared emission. This novel...
Description of Technology: Programed Death-Ligand 1 (PD-L1, also known as B7-H1 or CD274) is a cell surface protein that binds to Programmed Cell Death Protein 1 (PD-1, also known as CD279). An imbalance in PD-1/PD-L1 activity contributes to cancer immune escape. PD-1 is expressed on the surface of antigen-stimulated T cells. The interaction between PD-L1 and PD-1 negatively regulates T cell-mediated immune responses. It has been suggested that disrupting the PD-L1/PD-1 signaling pathway can be used to treat cancers. The aberrant expression of PD-L1 on multiple tumor types supports this suggestion. As a result, PD-L1 represents a strong target for the development of new anti-cancer therapeutics. Researchers at the NCI’s Laboratory of Molecular Biology have isolated three anti-PD-L1 single domain antibodies (also known as nanobodies), B2, A11, and F5 that target PD-L1. These nanobodies can be used either as independent agents or as the...
Essential stem cell maintenance genes, including Pax7, a transcription factor fundamental to preserving the high regenerative capacity of muscles, is induced via targeting DNA secondary structures. Problem: Tissue restoration is essential to maintain skeletal muscles after injury. Skeletal muscle regeneration is exclusively achieved by the bona fide residential stem cells known as muscle stem cells (MuSCs). External cues, such as muscle trauma, activate the quiescent MuSCs to undergo rapid expansion and differentiation to reconstruct damaged muscle. Aging, diabetes, obesity, cancer cachexia, and several muscle diseases, including muscular dystrophies, are associated with a loss of MuSC function and a significant decline in skeletal muscle regenerative capacity. Solution: MuSCs are essential for muscle maintenance and growth throughout life; exploiting the critical molecular regulators of these cells is vital to harness their...
Antibiotic Peptide de-extinction (APEX) is a deep-learning AI solution that can unearth ancient antibiotics to effectively combat superbugs and tackle antibiotic resistance on a global scale. Problem: Escalating antibiotic resistance around the globe has emerged as one of the pressing problems of our time, with antibiotic-resistant infections causing approximately 1.27 million deaths annually worldwide. Without effective new drugs, this number could surge to 10 million fatalities by 2050. Traditional drug discovery approaches have been unable to keep pace with the evolution of antibiotic-resistant bacterial strains, resulting in a critical shortage of novel antibiotics to combat these resistant pathogens. These developments can seriously jeopardize public health in the future. Solution: Researchers have developed a deep learning AI technology that analyzes a protein database of long-extinct organisms to rediscover lost,...
Investigators at the National Heart, Lung and Blood Institute have developed modified defensins that are resistant to degradation, have improved characteristics compared to unmodified defensins, and are promising candidates for pulmonary disease therapeutics. Defensins are small cationic peptides that defend the lung against pathogenic microorganisms and play an important role in innate immunity. However, during lung inflammation, defensin concentrations can reach levels that are cytotoxic for airway epithelial cells. Therefore, the development of methods to produce modified defensins that exhibit reduced cytotoxicity, while retaining the ability to stimulate the innate immune response, would be of potential therapeutic benefit for pulmonary diseases. The inventors have previously shown that a defensin, human neutrophil peptide 1 (HNP-1), is elevated in samples from the lungs of patients with inflammatory lung disease, and that the...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for three small molecules that target hRpn13, an overexpressed protein in certain cancers. Description of Technology: Over 35,000 new cases of multiple myeloma are diagnosed each year in the US. Standard of care and experimental therapies include monoclonal antibodies, immunomodulatory drugs, proteasome inhibitors and corticosteroids. While these therapies can be effective, a majority of patients experience relapse within four years. New proteasome-targeting drugs are needed to improve current myeloma treatments. Proteasome inhibitors function by interfering with a cell’s normal protein recycling process and induce apoptosis via multiple mechanisms. FDA-approved proteasome inhibitors exist with indications for the treatment of liquid cancers, specifically multiple myeloma and mantle-cell lymphoma. However, these drugs can induce...
The invention relates to a dengue virus tetravalent vaccine containing a common 30-nucleotide deletion (delta30) in the 3'-untranslated region (UTR) of the genome of dengue virus serotypes 1, 2, 3, and 4. The previously identified delta30 attenuating mutation, created in dengue virus type 4 (DEN4) by the removal of 30 nucleotides from the 3'-UTR, is also capable of attenuating a wild-type strain of dengue virus type 1 (DEN1). Removal of 30 nucleotides from the DEN1 3'-UTR in a highly conserved region homologous to the DEN4 region encompassing the delta30 mutation yielded a recombinant virus attenuated in rhesus monkeys to a level similar to recombinant virus DEN4delta30. This established the transportability of the delta30 mutation and its attenuation phenotype to a dengue virus type other than DEN4. The effective transferability of the delta30 mutation establishes the usefulness of the delta30 mutation to attenuate and improve the...
This CDC-developed invention relates to dengue vaccines that have been specifically developed for improved efficacy and directed immune response to avoid antibody-dependent enhancement (ADE) safety issues that, theoretically, may be associated with dengue vaccines and vaccinations. Dengue viral infection typically causes a debilitating but non-lethal illness in hosts. However, dengue hemorrhagic fever (DHF), the much more severe and life-threatening condition, is generally attributed to secondary dengue infections caused by a serotype different from the initial infection serotype by way of ADE. This effect, particularly notable in dengue viruses, should be given special consideration during vaccine design and construction. This in vivo -validated technology provides a strategy and mechanism for increasing the safety of dengue vaccines and diminishing the likelihood of such vaccines inadvertently harming a recipient due to ADE-mediated...
This technology includes a novel capsid protein for recombinant adeno-associated virus (AAV)-mediated gene transfer evaluation. We have identified a "fossilized" endogenous AAV sequence element (referred to as mAAV-EVE) within the germline of an ancient lineage of Australian marsupials and have cloned and sequenced mAAV-EVE orthologs from at least fifteen lineage-specific taxa. Using computational analysis of mAAV-EVE sequence alignments, we have inferred the coat protein sequence of a >25-million-year-old adeno-associated virus which circulated among host species sometime during the Eocene-Oligocene transition. This novel AAV coat protein sequence may provide the basis for recombinant AAV vectors with unique biological properties. Moreover, the method of derivation of the ancient marsupial AAV coat protein sequence may be used for any endogenous AAV sequences occurring within related taxa in sufficient number. Commercial...
The invention pertains to derivatives of docosahexaenoylethanolamide (synaptamide or DEA) and their use in inducing neurogenesis, neurite growth, and/or synaptogenesis. As such, these DEA derivatives can be used as therapeutics for neurodegenerative diseases such as traumatic brain injury, spinal cord injury, peripheral nerve injury, stroke, multiple sclerosis, autism, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis. The DEA derivatives of the invention have increased potency and hydrolysis resistance as compared to native DEA. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid accumulates in the brain during development, and has been implicated in learning and memory development. DEA, a metabolite derived from DHA, also has been shown to accelerate neuronal growth and development. In vitro studies in which neural progenitor cells were treated with DEA derivatives showed an...
Nanoparticles such as lipid-based nanoparticles (LNPs) represent a relatively new era of targeted drug delivery systems wherein these biocompatible particles can carry the drug(s) of interest to a specific tumor site. The new generation of nanoparticles, known as stealth nanoparticles, are engineered to have a coating of polyethylene glycol polymer (PEG) or other glycolipids that enable them to evade the immune system and have a longer circulation lifespan as well as improved bioavailability to diseased tissue and reduced non-specific toxicity. Scientists at the National Cancer Institute (NCI) have developed the formulation of novel stealth nanoparticles that have high stability and high payload capacity. These nanoparticles are vesicles made of binary lipid bilayer comprising phospholipid DC8,9PC and a PEGylated lipid such as DSPE-PEG2000. The vesicles can carry high amounts of payload of a hydrophobic photodynamic drug (PDT) such as...
Methods for generating single chain variable region Fragments (scFvs) for use as targeting agents for the treatment of infectious, inflammatory, and neoplastic diseases in dogs. Problem: Cancer is the leading cause of death in our current canine pet population. Previous studies have found that 45% of dogs aged 10 years or older and 23% of dogs of any age die from cancer. The gold standard of veterinary cancer therapy is systemic administration of chemotherapeutic agents that inhibit cell division and induce cell death. These agents are not tumor-specific and frequently cause adverse side effects which limit the dose that can be given and potentially the therapeutic efficacy. Solution: Dr. Nicola Mason has devised a patented method to generate and isolate canine scFvs for in vivo use as immune targeted therapeutics. These therapeutics could include, but are not limited to, those in the immune-oncology space including bi-specific...
This invention provides a rapid, sensitive and specific diagnostic tool for the detection of pathogenic fungi and subsequent species-specific discrimination. CDC scientists have developed nucleic acid probes to identify the six most medically important Candida species and endemic mycoses, and to differentiate them from other medically important fungi in a multi-analyte profiling system. Candida fungi are one of the leading causes of clinically-acquired bloodstream infections and, although improved antifungal compounds have been recently introduced, they have unique, species-specific treatment responses. This multi-analyte approach has the potential to simultaneously identify up to 100 different fungi in one assay. Additionally, the assay is quite cost effective in terms of resource input, time invested and technician labor. Used in conjunction with contemporary antifungal medications, this assay provides a very rapid and specific...
Summary: The National Cancer Institute (NCI) seeks research collaborations and/or licensees for the development of a CD276 antibody drug conjugate (ADC) for the treatment of solid tumors. Description of Technology: Angiogenesis is the formation of new blood vessels from pre-existing blood vessels. Angiogenesis occurs during normal growth and development (physiological angiogenesis) and during the growth of solid tumors (pathological angiogenesis). CD276, also known as B7-H3, is a cell surface tumor endothelial marker that is highly expressed in the tumor vessels of human lung, breast, colon, endometrial, renal, and ovarian cancer, but not in the angiogenic vessels of normal, healthy tissue. This differential expression makes CD276 an attractive target for cancer treatment due to the ability to selectively target pathological angiogenesis without impacting physiological angiogenesis. In fact, CD276-directed therapeutic antibodies may...
CDC and collaborative researchers have developed a device allowing for simultaneous measurement of smooth muscle contractile/relaxant activity and transepithelial potential difference (Vt) [or short circuit currents (Isc)] and resistance (Rt) within an intact airway in vitro . Investigation of the underlying mechanisms of lung diseases, such as asthma or cystic fibrosis, involves understanding the roles of airway smooth muscle and epithelium. Smooth muscle is involved in the control of the airway diameter; epithelium regulates the ionic composition of the liquid lining the airways through electrogenic ion transport and releases factors that regulate the ability of smooth muscle to contract. This invention allows for the measurement and study of pulmonary diseases under conditions retaining normal spatial relationships between all the cell types and an unmanipulated/undistorted tracheal airway wall. Further, the device permits...
Monoclonal antibody and immunotherapy use in prostate cancer Applications: Use of the monoclonal antibodies or functionally active fragments thereof for diagnosing the presence and the progression of prostate cancer in an individual. Use of the monoclonal antibodies or functional active fragments thereof for treatment of prostate cancer, especially for recurrent androgen-independent metastatic prostate cancer. Inventors: Mark Greene.
This technology identifies twenty five (25) new alternatively spliced transcripts of the BORIS gene. The transcripts lead to the expression of seventeen different protein isoforms with variable N- and C-termini encoded by BORIS gene locus. Differential expression levels of BORIS isoforms were observed in different cancers. While some BORIS alternative splice variants were expressed at different levels in all types of cancers, other expressed forms are specific to particular cancer(s). Commercial applications: Simple, rapid, RT-PCR based diagnostic test to detect BORIS isoforms in cancer patients.. Profiling of BORIS splice variants can be useful as a diagnostic tool for the detection of cancers.. BORIS can be a therapeutic target antigen for immunotherapeutic and/or siRNA based treatments for cancer.. BORIS can be used in combination with other established immunogens for immunotherapeutic treatment of several cancers.. Source...
Congenital hydrocephalus is a significant public health problem, affecting approximately one in 500 live births in the United States. Congenital hydrocephalus has an adverse effect on developing brain and may persist as neurological defects in children and adults. Some of these defects may manifest as mental retardation, cerebral palsy, epilepsy and visual disabilities. Improved diagnostics are needed for assessing the risks of developing this debilitating disease. The inventors have shown that RFX4_v3, a splice variant of the Regulatory Factor X4 (RFX4) transcription factor, is associated with the development of neurological structures. The reduction or absence of RFX4_v3 promotes the development of congenital hydrocephalus. This invention describes RFX4_v3 polypeptides and nucleic acids, as well as methods for detection of RFX4_v3 polymorphisms associated with congenital hydrocephalus. Also described are treatment methods including...
This CDC invention relates to primers and probes that specifically hybridize with Heartland virus (HRTLDV), a unique member of the genus Phlebovirus . It further relates to polyclonal antibodies specific for HRTLDV proteins. Serological detection assays using HRTLDV nucleic acid molecules, proteins, probes, primers, and antibodies are provided. Importantly, the HRTLDV genome can be engineered using reverse genetics to be attenuated, allowing development of a vaccine for other viruses within the Phlebovirus genus or Bunyaviridae family. Individual proteins or peptides of the HRTLDV can also be used in other FDA-approved virus backbones to act as vaccines. Further, since HRTLDV targets the bone marrow, disclosed HRTLDV delivery vehicles may be used to deliver therapeutic agents to the bone marrow. Commercial applications: Development of nucleic acid (RT-PCR) and serologic diagnostic assays for phleboviruses. Phlebovirus vaccines. Novel...
CDC researchers have developed monoclonal antibodies useful as diagnostics for diisocyanate (dNCO) exposure and for toxicity characterization of specific dNCOs. Currently, dNCOs are used in the production of all polyurethane products and are the most commonly reported cause of occupational-induced asthma and also linked to allergic contact dermatitis. Presumptive diagnosis of dNCO asthma is presently dependent on criteria such as work history, report of work-related asthma-like symptoms and nonspecific airway reactivity to methacholine challenge. This invention is a cost-effective, objective alternative for clinical assessment of occupational/environmental dNCO exposure in patient samples. These antibodies may also provide for passive-immunization and prevention of allergic contact dermatitis and/or asthma that can result from extended dermal exposure to dNCO contaminated surfaces and vapors. Further, the present technology allows for...
Anti-neoplastic drugs, also known as anti-cancer drugs or chemotherapy, are used in the treatment of many types of cancer. However, these drugs are harmful to healthy cells as well as the cancerous cells. Exposure of healthcare workers to anti-neoplastic drugs from contaminated surfaces and drug vials in hospitals and pharmacies is a continuing problem as the drugs can cause both acute and long-term effects. Although there are sensitive techniques to evaluate contamination, results from these tests take time and must be performed in a laboratory. CDC researchers developed a real-time detection kit that can be used in the workplace to test for anti-neoplastic drug contamination. The direct reading anti-neoplastic drug detector based on lateral flow immunoassay (LFIA) technology has been developed for the assessment of drug residues on surfaces. These detectors are incorporated into kits that allow workers to sample surfaces to assess...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for engineered chimeric snoRNA guides that recruit NAT10 to a specific target and cause directed acetylation of the target. They could be used to treat haploinsufficiency-associated disorders or diseases. Description of Technology: Haploinsufficiency (HI) is the loss of one allele of a gene. The resultant loss in associated protein expression/function is insufficient for a normal phenotype and manifests in a myriad of diseases. Such diseases include: [1] congenital malformations (e.g., eye defects, cleft lip/palate, etc.), [2] neurodevelopmental disorders (e.g., autism spectrum disorders, epilepsy, schizophrenia, etc.) and [3] disorders of maintenance and self-renewal. This latter category includes cancer predisposition syndromes, obesity, maturity onset diabetes of the young, and autoimmune disorders. In total, over 300 known human...
One of the most challenging hurdles in creating safe and effective new medicines for many diseases is finding drugs that are effective without causing off-target cardiac issues, such as cardiac arrythmias. In collaboration with NIDA, scientists at NCATS have developed a series of novel and highly specific dopamine D3 receptor agonists and antagonists that have potential to target and treat Parkinson’s disease, Schizophrenia, Depression, and substance-use disorders including opioid addiction. Important features of these novel chemical compounds are that they exhibit favorable drug-like properties that are likely to make them successful drug candidates, and have reduced human ether-à-gogo-related gene (hERG) liability and effect on potassium channels, which suggests that the compounds may perform better as Dopamine D3 receptor agonists due to a lower propensity to create cardiac arrythmias. The novel compounds comprise potent and highly...
CDC researchers have identified and characterized discrete flavivirus cross-reactive epitopes useful for improving serodiagnosis and vaccination of flaviviruses, such as dengue virus, yellow fever virus, Japanese encephalitis virus, West Nile virus and the tick-borne encephalitis viruses. The flavivirus envelope glycoprotein is one of the primary antigens inducing protective immunity in a host. Human flavivirus infections stimulate virus species-specific as well as flavivirus-genus cross-reactive immune responses. These cross-reactive antibodies create a serious problem for serodiagnosis, especially for secondary flavivirus infections, due to the difficulty of differentiating primary from secondary cross-reactive serum antibodies. Additionally, the presence of subneutralizing levels of flavivirus cross-reactive serum antibodies in an individual may result in a dramatic increase in the severity of secondary flavivirus infections via...
Description of Technology: Due to the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. The development of subtype-selective pharmaceutical small molecules to activate (agonists) signals regulated by D2-like receptors has been especially difficult. The inventors at the National Institute on Aging (NIDA) have recently synthesized a new generation of D3R selective agonists by applying a well-established bitopic molecular approach. Inventors were able to combine a primary pharmacophore (PP) with a secondary pharmacophore (SP) to generate compounds with high D3R subtype affinity and selectivity (e.g., compound 53). All newly synthesized compounds were tested in radioligand competition binding studies for D2-like receptor affinities (D2R, D3R, and D4R). Compound 53 and its eutomer, 53a were further evaluated...
shRNA library of 3 million sequences for identification of small-RNA therapeutic candidates, new targets and pathways, as well as conventional chemical-compound drugs in cell-culture disease models. Problem: ShRNA Drug Discovery: RNA interference (RNAi) using short hairpin RNA (shRNA) is commonly used to inhibit gene expression. shRNA-expressing libraries may have important applications in identifying RNA molecules/sequences with specific biological activity and thus therapeutic implications. Typically, shRNA libraries are limited to sequences that target single mRNAs. Because 7-nucleotide “seed” sequences within shRNAs are sufficient for partial inhibition of target mRNAs, shRNAs are inherently promiscuous. Thus, the single-gene-targeting approach is complicated by off-target effects, which diminish therapeutic indices, and fails to take advantage of multi-gene targeting, which enhances potency. Discovery of Drugs, Targets, and...
Summary: Scientists at the National Cancer Institute (NCI) have developed a novel tightly regulated drug-responsive, membrane-bound IL-12 cytokine platform, that enhances anti-tumor efficacy in adoptive cell therapy (ACT) with engineered T-cells (CAR, TCR, TILs) while improving safety. The NCI seeks research co-development partners and/or licensees to advance this technology toward clinical translation. Description of Technology: ACT offers hope for patients with refractory or metastatic cancers, but effectiveness is frequently undermined by the immunosuppressive tumor microenvironment and T-cell dysfunction. Interleukin-12 (IL-12), a powerful cytokine with strong anti-tumor properties, has long been recognized for its potential to invigorate T-cell responses within tumors. However, systemic administration of IL-12 results in severe toxicity. Further, prior gene therapy strategies failed to provide sufficient control over IL-12...
Treatment of B-cell acute lymphoblastic leukemia (ALL) and lymphoma using chimeric antigen receptors (CARs) targeting B-cell surface protein CD19 has demonstrated impressive clinical results in children and young adults. Despite the promising results from CD19 CAR therapy, up to 40% of patients, who initially achieve remission, eventually relapse. Relapse or non-response to CD19-directed CAR therapy may be due to low or diminished CD19 expression. Such patients would be predicted to benefit from CAR therapies targeting other B-cell surface proteins, such as CD22. Scientists at the National Cancer Institute’s (NCI) Pediatric Oncology Branch have developed a novel, bicistronic CAR construct targeting both CD19 and CD22 simultaneously. Specifically, the construct encodes both CD19 and CD22 on the same vector, ensuring comparable levels of targeting activity against both proteins. CAR-T cells produced with this construct eradicated...
Despite four decades of intensive research, a safe and effective HIV-1 vaccine remains elusive due to the extreme difficulty in eliciting broadly neutralizing antibodies (bNAbs), which recognize and block HIV-1 from entering healthy cells. Only rare natural HIV-1 envelopes (Envs) promote the activation and expansion of naive B cells expressing unmutated germline antibodies of various bNAb lineages, but they typically do so for a single lineage for the same neutralization site. To overcome this challenge, NIAID has designed and characterized two chimeric HIV-1 Env immunogens capable of simultaneously engaging multiple germline bNAb lineages. Both chimeric Env immunogens maintain native-like folding and engage two lineages of germline bNAbs directed against two independent sites of HIV–1 vulnerability. Commercial applications: Immunization: The dual-germline engager HIV–1 immunogens could be employed during the priming phase of an HIV...
An osteoarthritis treatment comprised of TGFa nanoparticles that penetrate cartilage and persist in the joint. Problem: Osteoarthritis (OA), a degenerative joint disease, is the most common form of arthritis, with over 32 million adults affected in the US alone. Despite its prevalence and debilitating nature, no cure or disease-modifying treatment exists. The epidermal growth factor receptor (EGFR) signaling pathway controls many key cellular functions, and mice lacking EGFR develop OA. Transforming growth factor alpha (TGFa) stimulates the EGFR pathway and reduces OA in mice. However, its short circulation lifespan drastically reduces efficacy. Solution: An engineered nanoparticle delivery system increases penetration of TGFa into the cartilage, prolongs retention of TGFa in the knee joint, and blocks OA progression in an animal model. Inventors: Zhiliang Cheng, Ling Qin, Yulong Wei.
Summary: The NCI seeks research co-development partners or licensees for monoclonal antibodies that specifically target cancer-expressed EGFR. Description of Technology: Epidermal growth factor receptor variant III (EGFRvIII) is a variant of EGFR that is an excellent target for immunotherapy because of its expression in cancer cells and not in normal cells. Inventors from the National Cancer Institute (NCI) have isolated seven mouse monoclonal antibodies that bind to the human EGFRvIII but not wildtype EGFR. These EGFRvIII antibodies can be used as either independent agents or targeting domains in recombinant immunotoxins (RITs), antibody-drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptors (CARs). Significantly, RITs using one of the antibodies (40H3) have shown potent killing in breast cancer cells and in epidermoid cancer cells, strongly supporting that the antibodies may be further developed as...
Enterovirus D68 (EV-D68) has been linked to the widespread outbreaks of respiratory illness and acute flaccid myelitis (AFM) in the United States and Europe in 2014, 2016, and 2018. Although EV-D68 is now the most frequently encountered enterovirus (41.1% of cases), with an estimated global prevalence of 4%, there are no specific, FDA-approved therapeutic interventions targeting this virus. Researchers at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Disease (NIAID) have identified four monoclonal antibodies that potently bind and neutralize multiple subclades of EV-D68, including B3 and A2 variants. Animal studies have indicated that these Rhesus macaque-derived monoclonal antibodies (mAbs) are likely to confer protection against respiratory illness in young children (particularly those under age 5) and in individuals with respiratory or immunocompromising conditions. Analyses conducted using...
The ubiquitin-proteasome system has recently been recognized to play a central role in tumor biology. Bortezomib, an inhibitor of the chymotrypsin-like activity of the proteasome, has clinical activity in a variety of hematologic malignancies and is FDA approved for use in Multiple Myeloma and Mantle Cell Lymphoma. The present invention for the first time describes that Eeyarestatins, a new class of small molecules, are potential anti-cancer agents. The compounds inhibit the deubiquitination of proteins by targeting the deubiquitination enzymes in the protein degradation pathway. More specifically, the inventors have demonstrated that the Eeyarestatins successfully kill different leukemia and lymphoma cell lines as well as leukemia cells isolated from patients with chronic lymphocytic leukemia by inducing the expression of Noxa, a pro-apoptotic member of the Bcl-2 protein family. Additionally, Eeyarestatins are active against cells...
Implantable foot device to restore feeling and reduce pain associated with diabetic nerve complications. Problem: Sixty to seventy percent of the 400 million diabetes patients worldwide suffer from nerve complications like distal sensory polyneuropathy (DSP), which is characterized by foot pain and loss of feeling. If left unchecked DSP progresses, resulting in gait instability, falls, and can even lead to amputation. Current treatments are limited, consisting of either pain medication or biofeedback devices to alleviate sensory loss. No individual therapeutic addresses both pain and sensory issues simultaneously. To further complicate matters, all current methods suffer from lack of patient compliance (as low as 36%). Solution: In response, the inventors developed a nerve stimulation device that treats both pain and loss of feeling. In addition, as an implantable device there are no compliance issues. Inventors: Firooz Aflatouni,...
Hematopoietic progenitor cells (HPC) are multi-potent hematopoietic lineage cells that can differentiate into any type of blood cell, including but not limited to erythrocytes, T cells, B cells, and natural killer cells. As such, they have high therapeutic potential in the fields of regenerative medicine and cancer immunotherapy, especially when generated from patient-derived induced pluripotent stem cells (iPSC). Currently, the most efficient protocol to produce HPCs is co-culturing human iPSCs (hiPSC) with mouse stromal cells as a two-dimensional (2D) monolayer. However, animal cells are not suitable for clinical application and two dimensional (2D) cultures are not physiologically accurate. Further, animal product free (xeno-free) systems are expensive and not efficient. Researchers at the National Cancer Institute (NCI) developed a novel approach to produce HPCs from hiPSCs using a human mesenchymal stem cell (hMSC) 3D co-culture...
A highly efficient method to genetically modify natural killer (NK) cells to induce expression of high affinity CD16 (HA-CD16) through mRNA electroporation, to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated by CD16+ NK cells following adoptive NK cell transfer, but most humans express CD16 which has a relatively low affinity for IgG1 antibodies. However, a single nucleotide polymorphism (SNP rs396991) in the CD16 gene, resulting in an amino acid substitution at position 158 (F158V), is associated with substantially higher affinity and superior NK cell-mediated ADCC than those with the 158F genotype. This HA-CD16-158V polymorphism has also been linked to enhanced ADCC capacity in vivo. The nearly 100% efficiency of our method resulted in: a) sustained surface expression of transgenes at high levels for up to 4 days without compromising NK cell cytotoxicity and viability; and b) augmented...
Streptococcus pneumoniae (S. pneumoniae) bacteria, or pneumococcus, can cause many types of illnesses. These range from ear and sinus infections to life-threatening conditions such as pneumonia, bloodstream infections, and meningitis. Pneumococci are surrounded by a polysaccharide capsule, which is thought to help it evade the immune system. Presently, over 90 known serotypes of S. pneumoniae have been identified, of which only a minority produce the majority of pneumococcal infections; a serotype is defined by a unique pneumococcal capsule structure. Currently available vaccines contain antigens made from capsular polysaccharides of 10, 13, or 23 common S. pneumoniae serotypes. CDC has discovered encapsulated strains of commensal Streptococcus species, S. mitis, S. oralis and S. infantis, that have capsules that are identical to pneumococcal capsules. From this, researchers developed compositions and methods from the species’...
This technology includes ten engineered human induced pluripotent stem cell (iPSC) lines with reported genes inserted into safe harbor sites for use in therapy and diagnostic screening assay development as well as basic stem cell biology research. These cell lines have the potential to differentiate into all cells in the body, and theoretically can proliferate/self-renew indefinitely. Commercial applications: Utilized in studies that could facilitate the development of cellular therapies, more effective drug treatments through their use as screening assays, and improved understanding of basic stem cell biology. Competitive advantages: The pluripotent nature of these cell lines gives them the potential to differentiate into all cells in the body, and proliferate indefinitely, giving them a wide range of uses. Source institute: NIAMS. Inventors: Rao, Mahendra.
A method for manipulating wasp venom peptide to maintain antimicrobial properties while reducing human toxicity. Problem: Almost 20% of global deaths ( ~ 11 million) are from sepsis, often caused by bacterial infections. 35,000 of these deaths are due to drug-resistant bacteria, which are becoming more prevalent. Drug-resistant bacteria are also dangerous in secondary infections. These drug-resistant infections pose a large threat during global pandemics such as the current COVID-19 pandemic. Therefore, there is a need for new and effective antibiotics. Toxins contained in venom have antibiotic potential, however these venoms are inherently toxic to humans. Solution: Modified wasp venom peptide has potent antibacterial activity while avoiding the toxicity of normal wasp venom. The modified peptide also reduces inflammation while activating an effective immune response to bacterial infection. Inventors: Cesar de la Fuente-Nunez,...
Summary: Researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development are highly motivated in seeking licensing and/or collaboration partners to develop therapeutic cell populations arising out of these technologies. An ideal partner would enter into both a Cooperative Research and Development Agreement (CRADA) and an exclusive license agreement towards commercialization of one or more therapies to treat various oncologies. Description of Technology: Immunotherapy is a cutting-edge new category of treatment that aims to harness and, in some cases, modify the patient’s own immune cells to improve their ability to cure diseases. It can be an effective approach for a variety of conditions, ranging from cancer to inflammatory diseases. However, a number of obstacles to the overall success of immunotherapy still exist. For example, reactivity against a target antigen can be attenuated or the lifespan...
Summary: NCI seeks research co-development partners and/or licensees for the development of recifin and its analogues as new chemosensitizing agents in adjunct therapies with topotecan, irinotecan and related chemotherapeutic agents. Description of Technology: Topoisomerase enzymes play an important role in cancer progression by controlling changes in DNA structure through catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. Therefore, topoisomerases are important targets for cancer chemotherapy. Many topoisomerase 1 (TOP1) inhibitors such as camptothecin, rinotecan, and topotecan are widely used anti-cancer agents that work by stabilizing the TOP1-DNA cleavage complex. Stabilization causes irreversible double-strand DNA breaks, eventually leading to the death of replicating cancer cells. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that plays a role in allowing cells...
The invention pertains to methods of increasing the density of carboxylic acids on the surface of a carbon nanoparticle that can be functionalized with biologically relevant molecules, such as antibodies or peptides, for biomedical applications. Advantageously, the method could increase functionalization of a nanoparticle by at least about 1x107 functional groups/g of nanoparticle. The method includes contacting an oxygen-containing functional group on a surface of a carbon nanoparticle with a reducing agent to provide a hydroxyl group; reacting the hydroxyl group with a diazoacetate ester in the presence of a transition metal catalyst to provide an ester and then cleaving the ester to provide a carboxylic acid group. The carboxylic acid can further be secondarily functionalized to an acyl chloride, an amide, pegylated, a biotinylate, a folate, a thiol, a maleimide, an active ester, an amine, a chelated gadolinium, an azide, an...
Technology Overview: While Adeno-Associated Viruses (AAVs) shows great promise in gene therapy applications for the treatment of inherited and acquired retinal diseases, a significant challenge to date has been the limitation of AAV vectors to transduce non-permissive retinal cells and to express in a single cell type. The inventors have generated... Inventors: Jean Bennett.
Novel therapeutic approach to reverse or prevent the progression of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)
Immuno-therapy has taken a lead among the new cancer therapeutic approaches. It is one of the most promising new therapeutic approaches that exploit the innate immune mechanism of an individual to fight against a certain disease. Natural killer (NK) cells are a form of cytotoxic lymphocytes which constitute a major portion of the innate immune system. NK cells have tumor cytotoxic properties independent of tumor specific antigens and have been shown in murine models to control and prevent tumor growth and dissemination. Inactivation of NK cells potentially allows cancer cells to evade host NK-cell-mediated immunity. Ligation of killer immunoglobulin like receptors (KIRs) by MHC class I on both normal and malignant tissues suppresses the function of NK cells. The present invention relates to treating cancer and other hyperproliferative disorders by administering an enriched composition of allogeneic or autologous (KIR/KIR ligand...
In nature, some beetle larvae possess specialized barbed hastate setae that serve as an entanglement defense mechanism and incapacitate other insects. CDC researchers have developed synthetic setae for control and entrapment of insects and other pests. While smaller synthetic setae can trap mosquitoes and small insects, larger “macro” setae can be used for entrapment of bats, rodents, etc. Once used, the setae can be "reset" by a vigorous shaking of the fabric. This solution to pest control would be long-lasting and non-toxic, with the additional benefit of avoiding the evolutionary selection of pesticide resistant organisms. Commercial applications: Insect and pest control agents. Population sampling and monitoring. Competitive advantages: Fine entanglement setae can be used anywhere insects congregate, including mosquito bed netting, resting boxes, curtains, or wall linings. Mosquitoes and other pests trapped in the setae will...
CDC researchers have developed a reverse transcription/semi-nested polymerase chain reaction (RT-snPCR) assay for diagnosis of enterovirus infections within clinical specimens. Clinical laboratories currently identify enteroviruses by virus isolation and subsequent virus neutralization tests, or serological assays. In addition to being time consuming, these approaches are labor, cost and material intensive. The enterovirus molecular diagnostic test is prepared in a kit form, consisting of three reagent preparations (three separate test steps), to which a technician adds enzymes and RNA extracted from a clinical specimen. This format is amenable to commercial manufacturing processes. The assay primers were designed for broad specificity and amplify all recognized enterovirus serotypes. In the course of assay development, PCR products have been successfully amplified and sequenced from cerebrospinal fluid, nasopharyngeal swabs, eye...
The noroviruses (formerly known as “Norwalk-like viruses”) are associated with gastroenteritis outbreaks, affecting large numbers of individuals each year. Emerging data are supporting their increasing recognition as important agents of diarrhea-related morbidity and mortality. The frequency with which noroviruses are associated with gastroenteritis as “food and water-borne pathogens” has led to the inclusion of caliciviruses as Category B Bioterrorism Agents/Diseases. Because the noroviruses cannot be propagated by any means in the laboratory, an important strategy in their study is to development of molecular biology-based tools and replication systems. This invention reports the isolation of the first recombinant, enzymatically-active proteinase and RNA dependent RNA polymerase (RdRp) complex for a human norovirus. This enzyme should facilitate studies aimed at developing therapeutic drugs for norovirus disease. Source institute:...
Cystic fibrosis (CF) is a common genetic disease that affects the entire body, producing thick, sticky mucus that clogs the lungs, pancreas, and other organs. It is the most common fatal genetic disease in the United States, and is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR). Researchers at NIEHS have developed a cell line, CF/T43, which was produced by infection of airway epithelial cells isolated from CF patients with an SV40T retrovirus. CF/T43 cells maintain the abnormal ion transport characteristics of CF while having proliferation capability beyond that of a primary epithelial cell culture. Key features of the CF/T43 cell line include the formation of functional tight junctions, reduced apical membrane chloride conductance, and activation of apical chloride channels by calcium ionophores but not by cAMP-dependent agonists. This cell line may be used for elucidation of the mechanisms of...
This technology includes irradiated Epstein-Barr virus-transformed lymphoblastoid cell lines (EBV-LCL) as feeder cells for the ex vivo expansion of natural killer (NK) cells. EBV-LCL feeder cells, altered by radiation to prevent uncontrolled growth, provide a supportive environment for NK cells to multiply effectively. This method addresses the challenge of obtaining sufficient quantities of functionally active NK cells, which are crucial components of the immune system known for their ability to target and destroy tumor cells and virally infected cells. The use of EBV-LCL feeder cells permits improved scalability and effectiveness of NK cell-based therapies for cancer and infectious diseases. Commercial applications: This method potentially allows for a more efficient expansion of NK cells compared to current techniques, resulting in a higher yield of cells for therapeutic use. Competitive advantages: This technology offers a...
This technology includes anti-PSMA antibody labeled with 177Lu, which has shown to be an effective treatment for prostate cancer. Several small molecules targeting PSMA were also evaluated in prostate cancer patients labeled with betta emitters such as 177Lu. The most common one is 177Lu-PSMA-617 which is under clinical evaluation in many countries. Usual treatment in patients in most clinical trials was composed of up to 3 cycles of 177Lu-PSMA-617. The limited data available suggest partial response rates of up to 70%–80% that was limited to as few as several weeks in some of the patients. Encouragingly, only stage 1 -2 hematologic toxicities and sporadically mild xerostomia and fatigue were reported as side effects. Commercial applications: This product will be of use in nuclear imaging and radiotherapy of PSMA-positive tumors, and the EB derivative can be used for increasing the blood half-life of small molecules targeting PSMA....
An efficient way to improve outcomes of bone marrow and umbilical cord blood transplants to increase survival in blood cancer patients. The invention works by expanding hematopoietic stem cells in culture using a defined medium with specific inhibitor combinations. Problem: Expanding hematopoietic stem cells (HSCs) is paramount in stem cell research and for clinical use of HSCs. However, HSC homeostasis is not well understood and methods for HSC expansion have so far required the use of complex and expensive cocktails of cytokines and/or support cells. Solution: Dr. Klein and his team developed a method to expand and maintain HSCs ex-vivo using available GSK3 and mTOR inhibitors potentially enabling production of a greater number of long term HSCs without the use of exogenous hematopoietic cytokines and other factors. This combination, in mice, increases the number of HSCs, improves the frequency of engraftment, and shortens the time...
Regulatory B-cells (Breg) play an important role in reducing autoimmunity and reduced levels of these cells are implicated in etiology of several auto-inflammatory diseases. Despite their impact in many diseases, their physiological inducers are unknown. Given that Bregs are a very rare B-cell, identifying factors that promote their development would allow in vivo modulation of Breg levels and ex-vivo production of large amounts of antigen-specific Bregs to use in immunotherapy for auto-inflammatory diseases. Researchers at NEI's Molecular Immunology Section developed a method for the ex-vivo production of Breg. The method of production involves treating isolated primary B-cells or B-cell lines with IL-35 to induce their conversion into IL-10, producing Breg. Using this method, B-regulatory cells can be produced in large quantity and used in a Breg-based therapy against autoimmune diseases including, but not limited to, uveitis and...
This CDC developed invention identifies an assay for extremely fast and sensitive detection of Bacillus anthracis lethal toxin (LTx), the toxin responsible for the lethal effects of anthrax infection. This assay has already been successfully tested in animals and will allow for early detection of anthrax exposure and screening of lethal factors to monitor anthrax toxicity, for example for vaccine trial candidates. LTx is composed of two proteins, protective antigen (PA) and lethal factor (LF). In one scenario, the assay effectively detects LF by first using magnetic protein G beads to capture and concentrate LF in samples, then testing for LF on the bead by reacting it with a peptide substrate designed to mimic LF's natural target. By using techniques such as mass spectrometry, FRET or liquid chromatography, this test can check for LF rapidly and with extraordinary specificity and sensitivity. Methodology and basic assay validation...
Summary: NCI seeks commercial partners to co-develop and/or license a novel method to identify neoantigen reactive T cells and TCRs. Description of Technology: Adoptive cell transfer (ACT) uses tumor infiltrating lymphocytes (TILs) that recognize unique antigens expressed by cancer cells (“neoantigens”). Neoantigen specific TIL administration in patients has resulted in long term regression of certain metastatic cancers. However, one of the challenges of ACT and engineered T cell receptor (TCR) therapies more broadly, is the identification and isolation of these mutation specific TILs and TCRs. Only a fraction of TILs in a given patient is known to be tumor reactive, while the majority are not useful for cell therapy. The current procedures for isolating neoantigen reactive TILs and TCRs are time consuming, labor-intensive, and lack sensitivity and specificity. Researchers at the National Cancer Institute (NCI) have developed a novel...
Hutchinson-Gilford Progeria Syndrome (HGPS) is a very rare progressive childhood disorder characterized by premature aging (progeria). Recently, the gene responsible for HGPS was identified (Eriksson M, et al. Nature 2003), and HGPS joined a group of syndromes — the laminopathies — all of which are caused by various mutations in the lamin A/C gene ( LMNA ). Lamin A is one of the family of proteins that is modified post-translationally by the addition of a farnesyl group. In progeria, the abnormal protein (progerin) can still be farnesylated, however, a subsequent cleavage is blocked. The present invention describes a possible treatment of laminopathies, cellular aging and aging-related conditions such as HGPS through the use of farnesyltransferase inhibitors (FTIs) and other related compounds. This treatment should lead to a decrease in the accumulation of abnormal proteins such as progerin in case of HGPS patients and therefore...
A method enabling facile synthesis and purification of RNA in a stable format that does not require cold chain distribution. Problem: The cold storage conditions required in the distribution of RNA-based therapies presents a major roadblock toward expanding the utility of these medicines. RNA is susceptible to degradation in aqueous environment and thus necessitates cryogenic (the production of materials at very low temperatures) transport and storage. The mRNA-based COVID-19 vaccines from Pfizer and Moderna, for instance, require storage at -70 °C and -20 °C, respectively. This amounts to a huge cost for maintaining the ultracold chain system. Therefore, a method enabling streamlined RNA synthesis and separation of products into a stable environment would mitigate such costs and widen the accessibility of the growing class of RNA-based treatments. Solution: Daeyeon Lee and his team developed a method for simultaneous RNA production...
The discovery and selection of suitable compounds for the treatment and prevention of autoimmune, inflammatory, and pain disorders is a significant challenge. Researchers at National Institute of Aging (NIA) mitigated this issue. They discovered and synthesized numerous novel fatty acid derivatives (novel small molecules) that may ameliorate these conditions and provide treatment options for these disorders. In a relevant rat model, the fatty acid derivatives developed by NIA demonstrated: increased activity. lower toxicity. greater stability. longer half-life. These beneficial results favorably compare to prior agents utilized for treating inflammation, autoimmune disorders, and/or pain. Certain of the disclosed fatty acid derivatives are capable of readily crossing the blood-brain barrier – providing an advantage specifically with respect to certain pain disorders. NIA is seeking statements of capability or interest from parties...
FGFR2 knockout is an embryonic lethal mutation and blocks limb bud initiation. Fibroblast Growth Factor Receptor 2 (FGFR2) is a high affinity receptor for several members of the FGF family. The FGFR2 gene was inactivated by deleting the entire immunoglobulin-like domain of the receptor which is critical for FGF binding and FGFR2 activity. Embryos that lack this domain die at E10-11.5 owing to a failure in chorioallantoic fusion or placental formation. The deletion also blocks limb bud initiation, establishing FGFR2 as the major receptor that mediates FGF signals during limb induction. Commercial applications: Mouse model to study developmental biology.. Source institute: NIDDK. Inventors: Deng, Chuxia.
FGFR3 knockout. Complete knockout of the FGFR3 gene, the gene in which missense mutants cause short statue achondroplasia, fails to restrain cartilage growth at the bone growth plate, allowing bones to elongate excessively but fail to ossify. Endochondral ossification is a major mode of bone formation. Cartilage proliferates, undergoes hypertrophy, begins to calcify, undergoes a program of cell death, and is replaced by osteoblasts. Fibroblast Growth Factor Receptor 3 (FGFR3) is expressed in cartilage rudiments of a wide variety of bones, and dominant missense mutations in the human FGFR3 gene cause achondroplasia, a common form of human dwarfism characterized by minimal proliferation of the growth plate cartilage in long bones. To determine the effect of complete absence of FGFR3 on bone development in mice, targeted disruption of the FGFR3 gene was accomplished by homologous recombination in embryonic stem cells. Remarkably, the...
FGFR4 knockout: Lung alveoli fail to develop normally in double mutant with FGFR4 and FGFR3 knockouts. The fibroblast growth factor receptor 4 ( fgfr-4 ) gene was inactivated by targeted disruption and homozygous recombination to study its possible role in lung development. FGFR-4 is expressed in postnatal lung, and FGFR-4 null mice have no obvious abnormalities. However, mice that are doubly homozygous for targeted disruptions of FGFR3 and FGFR4 display novel phenotypes, including pronounced dwarfism and lung abnormalities. The lungs of the double knockout mice are normal at birth, but they fail to develop secondary septae that delimit alveoli and increase the surface area of the lung. Although lung function is impaired, the double homozygous knockout mice are viable but sickly. Commercial applications: Model for the study of respiratory system and potential treatments.. Source institute: NIDDK. Inventors: Deng, Chuxia.
Several Fibroblast Growth Factor Receptor 4 (FGFR4) specific antibodies with binding affinity at the nanomolar range have been successfully developed at the Genetics Branch. These antibodies have been made into different formats of therapeutic including Antibody Drug Conjugate (ADC), Bispecific T cell engager (BiTE) ae well as Chimeric Antigen Receptor (CAR)-T cells. Proof of principle experiments have shown that when treated with FGFR4 positive tumor cells: FGFR4 specific antibodies were able to deliver cytotoxic agents and killed those cells. . CD3 FGFR4 BiTE were able to recruit T cells to kill those cells. . FGFR4 CAR-T cell was activated by cancer cells overexpressed FGFR4 and FGFR4 CAR-T cells were able to eliminate target cells both in vitro and in vivo . These findings are important in Rhabdomyosarcoma (RMS) as researchers at NCI's Genetics Branch found that high FGFR4 is overexpressed in RMS tumors compared with other normal...
The first therapeutic strategy designed to selectively disrupt platelet–tumor cell interactions, a key driver of cancer metastasis and post-surgical tumor spread.
Calcium is a key element in the regulation of many cellular processes, including muscle contraction, hormone excretion from gland cells, neurotransmitter release from nerve synapses, and the regulation of cellular metabolism. Elevated calcium levels are found in a number of diseases. The present invention relates to chromophoric or fluorescent dye calcium indicators that are superior for measurement of high concentrations of calcium ions due to their high dissociation constants. As a result of the high calcium ion dissociation constants, the perturbation resulting from introducing the indicator into the cell is greatly reduced. These calcium ion indicators can be measured by various techniques including 19F NMR spectroscopy, flow cytometry, and quantitative fluorescence techniques, and are useful for measuring calcium levels within the cytosol or within cellular organelles. Commercial applications: Research tool for quantifying...
CDC researchers have developed technology that consists of a simple and inexpensive technique for creating fluorescent labeled primers for nucleic acid amplification. Fluorescent chemical-labeled probes and primers are extensively used in clinical and research laboratories for rapid, real-time detection and identification of microbes and genetic sequences. During nucleic acid amplification, the "UniFluor" primer is incorporated into newly synthesized double stranded DNA. As a consequence, quenching of the dye's fluorescent signal occurs decreasing the fluorescence of the sample several fold. The decrease in fluorescence can be measured and observed using any commercially available nucleic acid amplification system that measures fluorescence (e.g., real-time PCR/thermocyclers). Because many real-time PCR applications require a multitude of fluorescently labeled primers or probes, the single-labeled primer technique also allows...
NeurologyOphthalmologyOncologyInfectious DiseaseImmunologyCardiometabolicInflammationBiologicDiagnostic / BiomarkerAI / ML
Summary: Investigators at the National Institute on Drug Abuse seek co-development partners and/or licensees for collection of mu opioid receptor (MOR) agonists as alternatives for existing compounds. Description of Technology: Although existing opioids are excellent analgesics and useful as positron emission tomography (PET) radiotracers, they come with debilitating side effects. These include addiction, respiratory distress, hyperalgesia, and constipation. Therefore, there is a need for alternatives with lower adverse effects. Investigators at NIDA have identified a novel fluorinated mu-opioid receptor agonist, Fluornitrazene (FNZ), a derivative of Etonitazene, that shows potent antinociceptive effects with low adverse effects. This compound does not accumulate in the brain or cause hyperalgesia. It has higher potency than morphine and fentanyl, but with fewer adverse effects. These characteristics make it and any derivatives useful...
Summary: The National Institute on Aging (NIA) seeks research co-development partners and/or licensees for the pre-clinical and clinical development of the compounds as anti-inflammatory therapeutics for systemic and neurodegenerative disorders. Description of Technology: Numerous systemic, as well as neurological disorders, have a hallmark inflammatory element that can drive disease progression. However, the use of currently available anti-inflammatory agents have failed to demonstrate efficacy as potential treatment for systemic and neurological disorders in clinical trials. The immunomodulatory imide drug (IMiD) thalidomide exerts anti-inflammatory effects through inhibition of tumor necrosis factor-alpha (TNF-α), which is a master regulator of the inflammatory response. Researchers at the National Institute on Aging (NIA) have synthesized novel thalidomide analogs possessing potent anti-inflammatory actions but, importantly,...
This CDC-developed technology is an aerosol preconcentration unit (APU) designed for use with spectroscopic detection techniques, including emission, Raman, or infrared spectroscopies. Most existing pulsed microplasma techniques, such as laser-induced breakdown, for aerosols rely mainly on filter-based collection and suffer from poor accuracy, precision, and detection limits and require long sample collection times. The APU is designed to address these drawbacks by pre-concentrating the aerosol particles on a tip of a microelectrode (a few hundreds of micrometers in diameter) to allow near-real time measurements with superior accuracy and precision. The APU is designed to be small, low-pressure drop unit for its use in a battery-operated, hand-portable instrumentation. The design significantly improves accuracy and precision of measurements relative to existing methods. The APU can be integrated with a microplasma source (such as a...
InflammationOphthalmologyOncologyInfectious DiseaseCardiometabolicBiologicDiagnostic / BiomarkerAI / ML
This invention claims antibodies and/or fragments thereof specific for hepatitis A virus (HAV) and the use of the antibodies in the diagnosis, prevention, and treatment of hepatitis A. Hepatitis A is the most common type of hepatitis reported in the United States, which reports an estimated 134,000 cases annually, and infects at least 1.4 million people worldwide each year. HAV is a positive sense RNA virus that is transmitted via the fecal-oral route, mainly through contaminated water supplies and food sources. HAV is thought to replicate in the oropharynx and epithelial lining of the intestines, where it initiates a transient viremia and subsequently infects the liver. Humoral immunity has been shown to provide an effective defense against Hepatitis A. Prior to the availability of the current inactivated virus vaccines, pooled human immune globulin preparations were routinely used to protect individuals traveling to areas of the...
Anti-inflammatory treatments, particularly those used in the context of viral infection, have been shown to greatly inhibit the overall immune response, which can result in poor immunity and failure to control or clear the infection. Novel alternatives that can effectively attenuate inflammation without the more serious side effects of steroid medications (e.g., global immune suppression, muscle weakness, etc.) may have substantial use across a wide range of disease areas. Francisella tularensis (FT), the causative agent of tularemia, exhibits a potent ability to induce rapid suppression of inflammatory responses in host cells. Building on prior work that demonstrated the ability of crude and enriched lipids from virulent FT strains to dampen inflammation triggered by a variety of sources, researchers at the National Institute of Allergy and Infectious Disease (NIAID) have developed FT lipid preparations with strong potential for the...
Angiogenesis is the formation of new blood vessels from pre-existing blood vessels. Angiogenesis occurs during normal growth and development, where it is known as physiological angiogenesis, and during the growth of solid tumors, where it is known as pathological angiogenesis. CD276, also known as B7-H3, is a cell surface tumor endothelial marker that is highly expressed in the tumor vessels of human lung, breast, colon, endometrial, renal, and ovarian cancer, but not in the angiogenic vessels of healthy tissue. This differential expression makes CD276 an attractive target for cancer treatment due to the ability to selectively target pathological angiogenesis without impacting physiological angiogenesis. In fact, CD276-directed therapeutic antibodies may have a higher degree of specificity for tumor vessels than current antiangiogenic agents that cannot distinguish physiological and pathological angiogenesis. Moreover, CD276 protein...
The tumor microenvironment consists of a heterogenous population of cells which includes tumor cells and tumor-associated stroma cells (TASCs). The TASCs promote tumor angiogenesis, proliferation, invasion and metastasis. Because stroma cells are found in both healthy and cancerous tissue, targeting the tumor stroma has been difficult due to the lack of targets with high tumor specificity. TEM8 (also known as ANTXR1) is a cell surface tumor endothelial marker that is most highly expressed in human tumor-associated stroma of pancreatic, breast, colon, lung, esophageal, bladder, and ovarian cancers. While low levels of expression are seen in healthy kidney, lung, and brain tissue, preliminary toxicity studies suggest limited, if any, toxic effects in these tissues. This differential expression makes TEM8 an attractive potential target for ADC development due to the ability to selectively target TASCs in many different tumor types....
Tumor necrosis factor receptor type 2 (TNFR2)-expressing regulatory T cells (Tregs), present in the tumor microenvironment, play an important role in tumor immune evasion. TNFR2 plays a crucial role in stimulating the activation and proliferation of Tregs, a major checkpoint of antitumor immune responses. In addition to its expression on Tregs, TNFR2 is also known to be overexpressed on some types of tumors and the survival and growth of these tumor cells is promoted by ligands of TNFR2. Therefore, antagonists of TNFR2 may act as checkpoint inhibitors that suppress Tregs but may also be cytotoxic to tumor cells whose survival is promoted by TNFR2 ligands. Targeting TNFR2 in this manner could be a feasible approach to the treatment of cancer and other immune diseases. NCI researchers have isolated and engineered a fully human TNFR2-specific monoclonal antibody capable of inducing cell killing of Tregs. The monoclonal antibody, named...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and licensees for a panel of five fully human antibodies against CD276 for the treatment of solid tumors. The collection also includes human CARs incorporating the antibodies for immunotherapeutic use. Description of Technology: Chimeric antigen receptor (CAR)-T cell therapy has been successful in leukemia but its use for the treatment of solid tumors has been challenging. CD276, also known as B7-H3, is a surface tumor marker highly expressed in the vasculature and surface of solid tumors. This strong expression in both areas of solid tumors makes CD276 a promising target for cancer therapies such as CARs. This technology comprises of a panel of five fully human antibodies (Y868, Y422, Y111, Y117, and YE5) against CD276 that can be incorporated into immunotherapies. The CARs generated using these antibodies were evaluated and compared to other known...
The fully human CAR targets mesothelin, a surface protein overexpressed in several cancer types. P4, a human antibody fragment that binds human mesothelin with high specificity, is fused to T cell signaling domains such as 28z. The T cells engineered to express this CAR are shown to shrink tumors in a mouse model bearing human ovarian tumors overexpressing mesothelin. Problem: Though engineered anti-mesothelin chimeric antigen receptor (CAR) T cells show encouraging pre-clinical results against certain cancer types, their clinical efficiency is stunted by their poor long-term persistence in infused human patients. Indeed, anti-mesothelin CARs are generally designed using mouse antibody fragments, which can trigger a detrimental immune response against the CAR T cells and destroy them (Maus et al, 2014), thus limiting their cancer destroying potential to a narrow time-frame. Solution: Instead of using a mouse antibody fragment for...
Immortalization of plasma cells leads to plasma cell malignancy diseases such as multiple myeloma (MM). B-cell maturation antigen (BCMA) is a protein that is preferentially expressed by malignant and normal B cells and plasma cells, butnot on other cells in the body. This limited expression profile suggests that BCMA is a promising target for anticancer therapeutics for cancers in which there is excess production of plasma cells and B cells. Researchers in the National Cancer Institute (NCI) Experimental Transplantation and Immunology Branch (ETIB) previously reported anti-BCMA CARs, which are currently being tested in the clinic for patients with multiple myeloma. While the results from clinical trials have demonstrated the efficacy of anti-BCMA CARs, the CAR being used in this clinical trial has an antigen recognition domain derived from mouse antibody; this allows for the possibility of an immune response by the patient against the...
A collagen-based nerve guidance conduit containing functional Schwann cell precursor-like cells derived from stem cells for the rapid treatment of peripheral nerve injuries. Applications: Treatment of peripheral nerve injuries Inventors: Anh Le, Qunzhou Zhang.
RNA interference (RNAi) is a naturally occurring post-transcriptional gene regulation process that represses the expression of specific genes. Exploiting endogenous RNAi by externally-delivered small-interfering RNA (siRNA) is a promising therapeutic for the treatment of various diseases representing several major unmet medical needs. Researchers at the National Cancer Institute (NCI) have developed DNA- and RNA-based nanoparticles that can induce RNA interference (RNAi), molecular imaging, or a combination thereof. Two DNA- or RNA-based nanoparticles are required to induce RNAi: one nanoparticle comprising up to six (6) DNA or RNA strands and the other nanoparticle comprising the complementary DNA or RNA strands. Upon association of two complementary nanoparticles, conformational changes (or “shape switching”) occurs to both nanoparticles. Nucleic acid duplexes are released upon shape-switching, which activates functional units...
Soluble forms of human CD4 (sCD4) inhibit HIV-1 entry into immune cells. Different forms of sCD4 and their fusion proteins have been extensively studied as promising HIV-1 inhibitors – including in animal models and clinical trials. However, they have not been successful in human studies due to their transient efficacy. sCD4 is also known to interact with class II major histocompatibility complex (MHCII) and, at low concentrations, could enhance HIV-1 infectivity. NCI researchers previously described a novel bispecific multivalent fusion protein called 4Dm2m which contains a single human CD4 domain (mD1.22) and a potent HIV-1 inhibitor (m36.4) (NIH Reference No. E-033-2013). mD1.22 is highly soluble and stable with good neutralizing activity without measurable interaction with MHCII. The NCI inventors have recently discovered new variants of 4Dm2m with increased stability and potency in mediating antibody dependent cellular...
GSD-Ia is an inherited disorder of metabolism associated with life-threatening hypoglycemia, hepatic malignancy, and renal failure caused by the deficiency of glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC). Current therapy, which primarily consists of dietary modification, fails to prevent long-term complications in many patients, including growth failure, gout, pulmonary hypertension, renal dysfunction, osteoporosis, and hepatocellular adenomas (HCA). Gene therapy-based techniques, which directly address the underlying genetic deficiency driving the disorder, offer the prospect of long-term remission in patients with GSD-Ia. Researchers at the NIH National Insitute for Childhood Health and Diseases have developed an adeno-associated viral (AAV) vector for the treatment of glycogen storage disease type Ia (GSD-Ia).This new AAV vector that expresses human G6Pase-alpha directed by the tissue-specific human G6PC promoter/enhancer...
Problem: There currently is no cure for Achromatopsia which affects up to 1: 50,000 patients in the US. Solution: Dr. Jean Bennett, MD, PhD, Kirby Professor of Ophthalmology at the University of Pennsylvania’s Perelman School of Medicine, one of the first investigators to develop a gene therapy for a rare inherited form of retinal blindness... Problem: There currently is no cure for Achromatopsia which affects up to 1: 50,000 patients in the US. Solution: Dr. Jean Bennett, MD, PhD, Kirby Professor of Ophthalmology at the University of Pennsylvania’s Perelman School of Medicine, one of the first investigators to develop a gene therapy for a rare inherited form of retinal blindness has developed a novel gene therapy for Achromatopsia, an inherited retinal degeneration characterized by the loss of cone photoreceptor function resulting in partial or total absence of color vision. Dr. Bennett and her team at Penn’s Center for Advanced...
AAV-mediated gene therapy approach for the treatment of Leber congenital amaurosis retinopathies resulting from NPHP5 mutations Problem: Leber congenital amaurosis (LCA) is an autosomal recessive disorder characterized by retinal dystrophy and severe visual impairment within the first year of life. LCA occurrence, while rare (1/50,000 – 1/33,000 of live births), is the leading cause of childhood blindness. Due to its early onset, LCA has been more challenging to treat as opposed to later onset retinopathies such as retinitis pigmentosa. To date, at least 15 different mutated genes have been associated with LCA. Of these 15 different genes, one (RPE65) is currently the subject of multiple ongoing gene therapy clinical trial studies. This particular gene mutation only accounts for approximately 16% of all LCA cases, therefore additional therapeutic approaches are needed so that a larger population of LCA patients have treatment options....
Gene therapy targeting disposal of toxic intracellular lipid debris and lipofuscin in wet age related macular degeneration. Problem: Macular degeneration is a genetic eye disorder that affects the retina resulting in progressive vision loss. Macular degeneration has two main forms, Stargardt’s macular degeneration (STGD) which affects juveniles, and age related macular degeneration (AMD) which affects older individuals. While a fairly small proportion of the population has STGD, with an estimated prevalence of 1 in 8,000 to 10,000, AMD affects a significantly larger segment at 2 million people in 2010 in the U.S. alone. There are currently few treatment options for macular degeneration disorders and therefore a serious need for innovative solutions. Solution: Work in the lab of Dr. Kathleen Boesze-Battaglia has resulted in a novel therapeutic approach which targets the underlying cause of macular degeneration vision loss, the...
Problem: Optic neuritis is a condition commonly observed in MS patients that leads to temporary or permanent visual decline following demyelination of the optic nerve and loss of retinal ganglion cells. Current therapies for MS and ON include immunosuppressive agents that mitigate the inflammatory component of disease. Unfortunately, these treatments... Problem: Optic neuritis is a condition commonly observed in MS patients that leads to temporary or permanent visual decline following demyelination of the optic nerve and loss of retinal ganglion cells. Current therapies for MS and ON include immunosuppressive agents that mitigate the inflammatory component of disease. Unfortunately, these treatments provide temporary symptomatic relief and, moreover, do not attenuate further neuronal loss. Solution: Jean Bennett, one of the first investigators to develop a gene therapy for a rare inherited form of retinal blindness, has developed a...
Description of Technology: Mutations in the cone rod homeobox (CRX) transcription factor lead to distinct retinopathy phenotypes, including early-onset vision impairment in dominant Leber congenital amaurosis (LCA). Adeno-Associated virus (AAV) vector-mediated delivery of a CRX cDNA under the control of a CRX promoter region partially restored photoreceptor phenotype and expression of phototransduction genes in an in vitro model of CRX-LCA. Gene therapy using the CRX-AAV vector to retinal organoids derived from induced pluripotent stem cells (iPSCs) of a patient with the dominant CRX-I138fs mutation partially restored expression of visual opsins and other phototransduction genes as revealed by immunohistochemistry and single cell RNA-sequencing. Retinal organoids from iPSCs of a second dominant CRX-LCA patient carrying a K88N mutation also revealed loss of expression of opsins and phototransduction genes as a common phenotype, which...
Recombinant adeno-associated virus (rAAV) expressing the gene for retinitis pigmentosa GTPAse regulation (RPGR) for the functional and structural rescue of photoreceptor cells of the eye as gene therapy for retinal degeneration and vision loss. Applications: Use in gene therapy for treatment of heritable X-linked retinitis pigmentosa cause by a mutation in the RPGR gene Inventors: Gustavo Aguirre, William Beltran, Artur Cideciyan, Samuel Jacobson.
Duchenne Muscular Dystrophy (DMD) therapy deletes let-7c miRNA binding sites using CRISPR-Cas9 based genome editing and AAV based delivery. Problem: Duchenne Muscular Dystrophy (DMD) is a fatal disease characterized by progressive muscle degeneration and weakness that affects 1 in 3,500 live-born males worldwide, and which ultimately causes death in the twenties due to respiratory or cardiac failure. It is caused by mutations in the DMD gene leading to an absence or severe reduction of dystrophin, a protein that helps keep muscle cells intact. There is currently no cure for DMD and all dystrophin-based approaches are associated with immunoreactivity limiting their long-term efficacy. Solution: Dr. Khurana and colleagues at University of Pennsylvania developed a method to upregulate utrophin, a dystrophin homolog protein, using CRISPR-Cas9 based genome editing and AAV-based delivery. The inventors have previously demonstrated in a...
This technology includes AAVS1 and C13 “safe harbor” transcription activator-life effector nucleases (TALENs) for drug screening or gene therapy applications. TALENs are engineered sequence-specific DNA endonucleases that can significantly enhance genome-editing efficiency by >100-1000 folds. “Safe harbor” such as AAVS1 safe harbor and C13 safe harbor is genome locus that allows robust and persistent transgene expression with no or minimal interference of endogenous gene expression and cell properties. Construction of TALEN-expression vectors that specifically target safe harbor locus will create high-efficiency and widely-applicable system to achieve precise genome engineering in human cells. Plasmids are available from Addgene: https://www.addgene.org/62196/ . https://www.addgene.org/62197/ . https://www.addgene.org/52637/ . https://www.addgene.org/52638/ . Commercial applications: Safe harbor, TALENs have broad applications on...
This technology relates to a method of generating artificial compositions that can be used as positive controls in a genetic testing assay, such as a diagnostic assay for a particular genetic disease. Such controls can be used to confirm the presence or absence of a particular genetic mutation. The lack of easily accessible, validated mutant controls has proven to be a major obstacle to the advancement of clinical molecular genetic testing, validation, quality control (QC), quality assurance (QA), and required proficiency testing. This method provides a consistent and renewable source of positive control material, as well as an alternative to patient-derived mutation-positive samples. Commercial applications: Generation of positive controls for molecular genetic tests, particularly for tests to detect cystic fibrosis. Competitive advantages: Positive controls can be included in new kits or packaged with pre-existing assays. Increased...
InflammationOphthalmologyOncologyNeurologyInfectious DiseaseImmunologyCardiometabolicCell/Gene TherapyDiagnostic / BiomarkerAI / ML
SMADs are a novel set of mammalian proteins that act downstream of TGF-beta family ligands. These proteins can be categorized into three distinct functional sets, receptor-activated SMADs (SMADs 1,2,3,5, and 8), the common mediator SMAD (SMAD 4), and inhibitory SMADs (SMADs 6 and 7). SMAD proteins are thought to play a role in vertebrate development and tumorigenesis. One of the research tools our NIH inventors have prepared is the Smad3-null mice model, created by disrupting exon 8 on the Smad3 gene. Symptomatic mice exhibit leukocytosis, with massive inflammation and pyogenous abscess formation adjacent to mucosal surfaces. Smad3 plays an important role in mediating TGF-beta signals in T lymphocytes and in neutrophils, and demonstrate that Smad3 deficiency results in immune dysregulation and susceptibility to opportunistic infection, ultimately leading to the lethality of the mice between 1 and 8 months. TGF-beta signals also play a...
Dengue virus is a positive-sense RNA virus belonging to the Flavivirus genus of the family Flaviviridae. Dengue virus is widely distributed throughout the tropical and semitropical regions of the world and is transmitted to humans by mosquito vectors. Dengue virus is a leading cause of hospitalization and death in children in at least eight tropical Asian countries. There are four serotypes of dengue virus (DEN-1, DEN-2, DEN-3, and DEN-4) that annually cause an estimated 50-100 million cases of dengue fever and 500,000 cases of the more severe form of dengue virus infection known as dengue hemorrhagic fever/dengue shock syndrome (DHFIDSS). This latter disease is seen predominately in children and adults experiencing a second dengue virus infection with a serotype different than that of their first dengue virus infection and in primary infection of infants who still have circulating dengue-specific maternal antibody. A vaccine is...
This technology includes genetic manipulation of natural killer (NK) cells to express thrombopoietin receptor (c-MPL) growth factor receptor as strategy to augment NK cell proliferation and anti-tumor immunity. Many investigational adoptive immunotherapy regimens utilizing NK cells require the administration of IL-2 or IL-15 cytokines to support the survival and function of the cells in patients, however administration of these cytokines causes a number of serious dose-dependent toxicities. In the presence of thrombopoietin (TPO) ligand, lentiviral transduction of primary human NK cells to express c-MPL enhanced in vitro cellular proliferation and increased degranulation and cytokine production towards target cells. Data from our study could be translated to a clinical trial setting, where the infusion of genetically modified c-MPL-expressing NK cells is followed by the off-label administration of an FDA-approved TPO-mimetic (e.g.,...
NIH investigators, for the first time, identified specific mutations associated with stuttering. These mutations are located within the genes encoding three enzymes, Glc-NAc phosphotransferase catalytic subunit [GNPTAB], Glc-NAc phosphotransferase recognition subunit [GNPTG], and N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase [NAGPA]. Together these constitute the pathway that targets lysosomal enzymes to their proper location. This pathway is associated with lysosomal storage disorders, and thereby this discovery provides potential novel therapeutic targets for amelioration of stuttering. This discovery has the potential to facilitate DNA-based (micro-array) testing among individuals who stutter, as well as enzyme-replacement therapy and small-molecule chaperone therapy for treatment of stuttering. The mutations described in this invention may account for up to 5-10% of this disorder in individuals who stutter,...
Cancer cells can spread to various regions in the body in a process called metastasis which is associated with non-responsive to treatment and thus reduced survival. Identifying the markers of metastasis has been a major concern in the field of cancer diagnosis and therapy. Interestingly, research has shown that there is an increase in myeloid progenitors and myeloid cells at various stages of metastasis in an attempt by the immune system to suppress cancer cells. This presents a promising technology for cancer immunotherapy. Researchers at National Cancer Institute (NCI) developed a platform to culture myeloid cells from murine bone marrow cells and apheresed human peripheral blood. Myeloid cells were modified to express IL-12 to enhance anti-tumor immunity, limit inflammatory response, recruit T cells to sites of interest and specifically target and kill tumors. The inventors used these genetically modified myeloid cells (GEMys) in...
A method of detecting DNase I hypersensitive sites ((DHS) in a single cell or very small number of cells, including cells recovered from formalin-fixed paraffin-embedded (FFPE) tissue slides of patient samples. DHS has revealed a large number of potential regulatory elements for transcriptional regulation in various cell types. The application of DNase-Seq techniques to patient samples can elucidate pathophysiological mechanisms of gene function in a variety of diseases as well as provide potentially important diagnostic and prognostic information. Unfortunately, the current DNase-Seq techniques require large number of cells and are applicable only to larger biopsies and surgical specimens. This technique, called Pico-Seq, allows detection when only very small population of cells are available, such as rare primary tumor cells and circulating-tumor-cells, isolated by a variety of methods. Pico-Seq uses conditions capable of restoring...
The National Institute on Drug Abuse (NIDA) is seeking interested parties to license or co-develop GDNFOS peptides and non-coding RNAs as therapeutic agents for neurodegenerative diseases. Glial cell line-derived neurotrophic factor (GDNF) is a small human protein encoded by the GDNF gene. GDNF has been effective therapy in laboratory animal models of Parkinson's disease and protects several types of neurons in the brain and peripheral nervous system. Researchers at the NIDA have discovered primate-specific GDNFOS, encoded by the opposite strand of glial cell derived neurotrophic factor (GDNF) gene. The GDNFOS gene encodes for novel peptides. These secreted growth proteins have potential neurotrophic activity and were found to be reduced in the middle temporal gyrus of Alzheimer's disease patients, and they might play a synergistic role in neuroprotective effects of GDNF in the human brain. The NIDA inventors have also developed an...
This technology is a collection of small molecule activators of a genetically defective version of the enzyme called glucocerebrosidase (GCase), which causes Gaucher disease. Gaucher disease is a rare disease affecting 1 in 40,000 babies born. Ashkenazi Jews of eastern European descent (about 1 in 800 live births) are at particular risk of carrying this genetic defect. It is caused by inherited genetic mutations in the gene that encodes GCase, which result in reduced activity of the enzyme. This enzyme is normally made and then transported to an organelle called a lysosome, which is dedicated to the degradation and disposal of molecules the cell no longer needs. GCase is responsible for the breakdown of a fatty material called glucocerebroside (or glucosylceramide). The accumulation of this lipid occurs inside specific cells called macrophages and macrophage-derived cells. The disease has been categorized into three types:...
Gaucher disease is a rare lysosomal storage disease that is characterized by a loss of function of the glucocerebrosidase (GCase) enzyme, which results in a decreased ability to degrade its lipid substrate, glucocerebroside. The intracellular build up of this lipid causes a broad range of clinical manifestations, ranging from enlarged spleen/liver and anemia to neurodegeneration. In Gaucher disease, the loss of GCase function has been attributed to low levels of the protein in the lysosomal compartment, resulting from improper GCase folding and transport. Also, mutations in the GCase gene have been linked to some forms of Parkinson's disease, and may also be involved in other proteinopathies. This technology describes a collection of salicylic acid-derived small molecules that act as chaperones to activate proper GCase folding and subsequent transport from the endoplasmic reticulum into the lysosome. Unlike many other small molecule...
This technology provides novel antibodies and methods for diagnostics and treatment of disorders arising from dysregulation of the immune system using antibodies directed against glucocorticoid-induced tumor necrosis factor receptor family-related receptor ligand (GITRL). Also available are hybridomas producing anti-mouse GITRL monoclonal antibodies (clone 5F1). Glucocorticoid-induced TNFR family-related receptor (GITR, also known as TNFRSF18) is expressed on the surface of responder T cells (CD4+CD25- or CD8+CD25- T cells). Upon activation of the immune response, GITR is up-regulated and binds to its ligand, GITRL (also known as TNFSF18), which enhances the immune response. The inventors have developed anti-GITRL monoclonal antibodies that block the interaction between GITR and GITRL, and have demonstrated in in vitro experiments that administration of these blocking antibodies can suppress the immune response. These antibodies may...
Griffithsin is a potent anti-viral protein with activity against HIV, HCV, Sars, HSV 1 & 2 and other viruses. It is active against HIV and HCV at picomolar concentrations. Griffithsin is moving into clinical trials as an anti-HIV microbicide. Based on the structure of griffithsin and the necessities of pharmaceutical product development and regulatory approval, certain mutations in the sequence of griffithsin have been generated which could add to the stability and solubility of the protein. These mutants have all been tested for biological activity, solubility and thermal stability. They possess modified physiological attributes that would be advantageous for subsequent development for both systemic and topical administration. Scientists in NCI's Molecular Targets Laboratory and collaborators modified the griffithsins to have a mutation position #77 (Met), which eliminates the possibility of Methionine oxidation at this...
Generation of a floxed Gnsa gene for the G-protein Gs alpha (G s alpha) for the construction of conditional knockout mice. The heterotrimeric G protein G s alpha couples many receptors to adenylyl cyclase and is essential for hormone-stimulated cAMP generation. Previous mouse models with germ-line mutations in Gnas , the gene that encodes G s alpha had limited usefulness in trying to decipher the role of G s alpha pathways in specific tissues since only heterozygotes were viable and could be analyzed. Analysis was further complicated by the fact that G s alpha is imprinted expressed in many metabolically active tissues. G s alpha-floxed mice were generated so that the metabolic effects of G s alpha deficiency could be examined in specific tissues. Exon1, which is specific for G s alpha, was surrounded with loxP recombination sites. Liver-specific knockouts of G s alpha were obtained by mating the G s alpha-floxed mice with albumin...
Details for this material are provided in the NIH AIDS Reagent Program Catalog (Catalog# 11445): https://www.aidsreagent.org/reagentdetail.cfm?t=expression_vectors&id=210 . Commercial applications: A research material that can be used in the development of assays, validation of products or in quality control.. Competitive advantages: Speed up product development with NIH developed material that has already been tested and validated.. Source institute: NIAID. Inventors: McKee, Krisha, Li, Yuxing, Wyatt, Richard, Mascola, John.
CDC scientists developed immunogenic multi-clade, multivalent (HIV1MCMV) recombinant constructs for use as HIV-1 vaccines. These polypeptides include immunogenic CTL, T- and/or B-cell determinants that are capable of eliciting broad and effective immune responses against diverse subtypes of HIV-1. It is believed that these HIV-1 constructs provide universal vaccines, capable of effective use in any part of the world affected by the HIV-1 epidemic. The construct contains specific cellular targeting epitopes that allow optimized antigen processing and recognition, and the design of the construct allows for the addition or deletion of epitopes. Additionally, the construct may be used to develop multi-pathogen vaccines by combination with other epitope-based constructs. Commercial applications: Development of HIV-1 vaccine. Competitive advantages: Allows easy epitope-tailoring. Broad spectrum protection against HIV-1. Unlike other...
Soluble forms (sCD4) of human CD4, the HIV-1 primary receptor, are potent HIV-1 entry inhibitors. Both four-domain (D1-4) and two-domain (D1D2) sCD4 and their fusion proteins have been tested as candidate therapeutics in animal models and in human clinical trials and were well tolerated by patients with no significant clinical or immunologic toxicities and exhibited significant inhibitory activities. However, their activities were transient and the virus rapidly rebound. Additionally, sCD4 is known to interact with the class II major histocompatibility complex (MHCII) and, at low concentrations, it could enhance the HIV-1 infectivity. Researchers at the National Cancer Institute’s Nanobiology Program generated a novel polypeptide comprising a single human CD4 domain (mD1.22) that is highly soluble, stable and shows significantly increased neutralizing activity without measurable interaction with MHCII. Competitive Advantages: Enhanced...
Summary: The NCI is seeking research co-development and/or licensees for the HLA-A*01:01 restricted human T-cell receptor recognizing the NRAS Q61K hotspot mutation. Description of Technology: Mutation of amino acid 61of the neuroblastoma rat sarcoma viral oncogene homologue (NRAS) is a known driver of oncogenesis in melanoma. Glutamine (Q) to lysine (K) mutation at this position of NRAS is prevalent in approximately 10% of all melanoma cases and associated with aggressive tumors and low patient survival. Therefore, Q61K mutated NRAS is an important candidate for targeted therapies, including cellular immunotherapy. National Cancer Institute scientists developed a T-cell receptor (TCR) specific for NRAS Q61K for use in adoptive cell transfer (ACT) T-cell immunotherapy against melanoma. T cells reactive to NRAS Q61K were screened and isolated from tumor infiltrating lymphocytes of a melanoma patient with this mutation and the human...
Summary: The National Cancer Institute (NCI) seeks co-development partners and/or licensees for a collection of T cell receptors (TCRs) that specifically target PIK3CA mutations to treat patients with tumors expressing these mutations in the context of HLA-DPA1*01:03:01, HLA-DPB1*04:01:01 or HLA-DRB1*04:01. Description of Technology: Phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha gene, also known as PIK3CA, makes a subunit of the PIK3 enzyme with various cellular functions. Mutations in the PIK3CA can result in the growth of cells through overactivation of the PIK3 enzyme and are associated with the development of several forms of cancers. Indeed, PIK3CA mutation is the third most common mutation in epithelial cancers. Previous studies attempted to inhibit the activity of mutant PIK3CA using both small molecules and monoclonal antibodies. However, these studies showed limited in vivo efficacy in treating tumors...
Bitter taste has evolved in mammals as a crucial, important warning signal against ingestion of poisonous or toxic compounds. However, many beneficial compounds are also bitter, and taste masking of bitter tasting pharmaceutical compounds is a billion dollar industry. The diversity of compounds that elicit bitter-taste sensations is very large and more than two dozen members of the T2R bitter taste receptor family have been identified. Individuals are now known to be genetically predisposed to respond or not to respond to the bitter taste of a number of substances. For example, large individual differences in the perception of bitterness have been well documented in compounds as different as nicotine, thiocyanates such as those found in cruciferous vegetables, and many bitter beta-glucopyranosides. This may have broad implications for nutritional status and tobacco use and common allelic variants of a member of the T2R bitter taste...
Heartland virus (HRTV) is a novel tick-borne virus first discovered in 2009 that causes flu-like symptoms such as fever, headaches, fatigue, muscle aches, and diarrhea. Patients with HRTV often have low white blood cell counts, low platelet counts, and abnormal liver function tests which can become severe. Cases of Heartland virus disease have been identified in the Midwestern and southern United States. There are no vaccines to prevent or medications to treat Heartland virus infections. HRTV presents symptoms and generates a similar immune response to other tick-borne viruses, making diagnosis difficult. In order to develop a diagnostic assay that can detect HRTV and distinguish it from other infections, CDC scientists developed and characterized anti-HRTV murine monoclonal antibodies. These monoclonal antibodies (mAbs) react to the viral nucleocapsid (N) protein. The mouse monoclonal antibodies can detect both recent and past...
Antibody drug conjugates (ADC) can demonstrate high efficacy as cancer therapeutics, however, much more can be done to improve their efficacy and safety profile. Site-specific antibody drug conjugation is a promising way to do this. Scientists at the NCI’s Laboratory of Experimental Immunology have identified a fully human monoclonal antibody, m860, that binds to cell surface-associated Her2 with affinity comparable to that of Trastuzumab (Herceptin) but to a different epitope. In addition, the scientist developed a site-specific glycan engineering method to conjugate the antibody to the small molecule drug auristatin F. The ADC prepared though this site-specific approach shows very good stability, cell surface binding activity and also potent specific cell killing activity against Her2 positive cancer cells, including Trastuzumab resistant breast cancer cells. This ADC has the potential to be developed as a targeted therapeutic for...
Cancer affects approximately 10 million people globally, with breast and lung cancer accounting for 25% of cancer incidences. Assuming over expression of Her2 is responsible for 25% of the breast cancer and lung cancer, and then the estimated market is about one million. The estimated price of Lapatinib, a small molecule tyrosine kinase inhibitor, is $5000/ dose (500mg) and the total market will be more than one trillion ($5000 * 365 * 1 million) dollars worldwide. Applications: Anti-cancer drug: The development of acquired resistance to anti-cancer drugs is one of the major limitations of anti-cancer therapy. The invention provides a novel class of Her2 and EGFR inhibitors that might halt the resistance to current tyrosine kinase inhibitors hence increase treatment efficacy. In addition, the discovered compounds exhibit great specificity against Her2/EGFR activity by selectively binding to only dimeric Her2. This might cause less...
The vast majority of people infected with Hepatitis C Virus (HCV) will have chronic infection. Over decades, this can lead to liver disease and liver cancer. In fact, HCV infection is the leading cause of liver transplants in the U.S. Several new drugs have recently come into the market that have changed the HCV treatment paradigm. However, the effectiveness of these new drugs can vary depending on the HCV genotype. Furthermore, all oral, interferon free therapeutic regimens for HCV infection will need combinations of drugs that target different aspects of the HCV life cycle. Thus, there is still the need for additional new therapeutics against HCV. The subject technologies are aryloxazole based small molecules that are potent inhibitors of HCV infection and replication. The compounds exhibit synergy with currently available therapeutics for HCV and represent a new class of anti-HCV compounds. The compounds affect the entry step of...
Antimicrobial peptides computationally mined from the human proteome. Problem: Novel antibiotics are needed to counter the emergence of drug-resistant bacteria as traditional discovery approaches have not yielded new classes of antimicrobials for decades. Antimicrobial resistance (AMR) is a growing public health concern and, thus far, no significant technological advance has capitalized on this market. Solution: The inventors developed an algorithm to mine the human proteome for the first time as a source of antibiotics. The human proteome contains a plethora of peptides that conduct countless functions. Here, the inventors discovered that many of these peptides have antimicrobial activity outside of their primary function in the cell, and these newly discovered antimicrobial peptides (AMPs) do not readily select for bacterial resistance and display potent anti-infective activity in preclinical mouse models. Inventors: Cesar de la...
Mesothelin is a cell surface protein that is an excellent target for immunotherapy because of its limited expression on normal tissues and its high expression on many cancers, including mesothelioma, cholangiocarcinoma, pancreatic, ovarian, lung, stomach, bile duct, and triple-negative breast cancer. Researchers at the National Cancer Institute’s (NCI) Laboratory of Molecular Biology have isolated two anti-mesothelin single domain antibodies (also known as nanobodies), A101 and G8. These antibodies have been isolated from newly developed camel single domain (VHH) libraries by phage display and have been used to shown to specifically target mesothelin-expressing cell lines with high affinity. Additionally, these mesothelin antibodies can be used as either independent agents or targeting domains in recombinant immunotoxins (RITs), antibody-drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptors (CARs)....
Pancreatic cancer is the fourth most common cause of death from cancer in the U.S. The overall 5-year survival rate for this disease is 8.5%. Glypican-1 (GPC1), a cell surface heparan sulfate proteoglycan protein that is overexpressed in pancreatic cancer. Due to this preferential expression, GPC1 represents a potential candidate for targeted therapy for patients with pancreatic cancer and other GPC1 expressing cancers such as prostate cancer. Researchers at the National Cancer Institute’s (NCI) Laboratory of Molecular Biology have developed and isolated two new antibodies that target GPC1 (HM2 and D4). These new antibodies have been shown to specifically target GPC1-expressing cell lines. These GPC1 antibodies can be used as either independent agents or targeting domains in immunoconjugates such as recombinant immunotoxins (RITs), antibody-drug conjugates (ADCs), chimeric antigen receptors (CARs), bispecific antibodies, etc....
Neuroblastoma is a rare pediatric cancer with approximately 1,000 new cases arising annually. Current therapies have a less than forty-five percent (45%), three-year survival rate which demonstrate a need for a more effective treatment against this disease. Glypican-2 (GPC2) is a cell surface protein that is preferentially expressed in pediatric cancers including neuroblastoma, which makes GPC2 an attractive candidate for targeted therapy. Researchers at the National Cancer Institute’s (NCI) Laboratory of Molecular Biology have developed and isolated two new antibodies that target GPC2 (CT3 and CT5). These new antibodies have been shown to specifically target GPC2-expressing neuroblastoma, medulloblastoma, and retinoblastoma cell lines. These GPC2 antibodies can be used as either independent agents or targeting domains in recombinant immunotoxins (RITs), antibody-drug conjugates (ADCs), and chimeric antigen receptors (CARs)....
Summary: The NCI seeks licensing and/or co-development research collaborations for CD276-targeting camel nanobodies. Description of Technology: CD276 (also called B7-H3) is a pan-cancer antigen expressed in multiple solid tumors and an emerging cancer target. CD276 protein is overexpressed in pancreatic cancer, prostate cancer, breast cancer, colon cancer, lung cancer, and brain tumors (such as neuroblastoma) – making it an ideal target for cancer therapy. Investigators at the National Cancer Institute (NCI) have isolated a panel of anti-CD276 single domain antibodies (also known as nanobodies) from novel camel and rabbit single domain (VHH) libraries by phage display. Nanobodies are the smallest known antigen-binding fragments of antibodies. Due to their small size, high solubility, thermal stability, refolding capacity, and relatively easy tissue penetration, they have great potential as medical applications and research tools....
This technology includes a novel concept and design for a lipoprotein targeting protease inhibitor for the treatment of Alpha-1-antitrypsin (A1AT) deficiency. A1AT deficiency occurs in about 1 in 2500 individuals in the United States and Europe, and people with this condition develop severe liver disease and emphysema/chronic obstructive pulmonary disease (COPD). Current treatment involves intravenous infusion of purified human A1AT protein, which is very expensive and only modestly effective. A recent study has demonstrated improvement in A1AT treatment effectiveness in a mouse model of emphysema by pre-incubating A1AT with high density lipoprotein (HDL) particles prior to infusion. This resulted in improvements in lung morphology and inflammatory markers in the lung compared to A1AT treatment alone. The mechanism for this improvement in function of A1AT when bound to HDL is believed to be increased trafficking of A1AT to the lung....
Optimized IGF-1 isoforms have been developed with improved potency in producing muscle hypertrophy. Problem: Insulin-like growth factor I (IGF-I) is a key regulator of muscle development and growth. However, the complexity of IGF-1 activity is modulated by extensive alternative splicing and glycosylation. Solution: A former Penn researcher, Dr. Elisabeth Barton, generated new forms of recombinant IGF-I (rIGF-1). In contrast to the work that has focused on the independent actions of the C-terminal E-peptide of IGF-I, which have modest activity, require the IGF-I receptor, and can be detrimental to muscle strength, the new IGF-I forms include both the mature IGF-I protein and the E-peptide as a single protein. Further, the sites for glycosylation have also been eliminated, affording the production of a single and potent pro-IGF-I form. The pro IGF-1 form is more potent and demonstrates enhanced IGF-1R activation both in vitro and in...
The National Cancer Institute Laboratory of Molecular Biology seeks parties for collaborative research to co-develop and commercialize antibody drug/toxin conjugates as liver cancer therapy and diagnostics. There is great interest and value in developing more sensitive and efficient agents for earlier detection of hepatocellular cancer (HCC). Glypican-3 (GPC3) is a cell surface heparin sulfate glycoprotein that is expressed on the vast majority of HCC cells. The correlation between GPC3 expression and HCC makes GPC3 an attractive candidate for studying the disease progression and treatment of HCC. The presence, progression, and treatment of HCC can potentially be monitored by tracking the level of GPC3 expression on cells. This can be accomplished using GPC3-specific monoclonal antibodies such as those NCI researchers generated for the cell surface domain of GPC3 (YP6, YP7, YP8, YP9 and YP9.1). Competitive Advantages: Sub-nanomolar...
Mesothelin is a cell surface protein that is highly expressed in aggressive cancers, such as malignant mesothelioma, ovarian cancer and pancreatic cancer, lung cancer, breast cancer, cholangiocarcinoma, bile duct carcinoma and gastric cancer. Because of this selective expression, mesothelin is an excellent candidate for targeted therapeutics, such as monoclonal antibodies (mAbs) and chimeric molecules. Current anti-mesothelin therapeutic mAb candidates bind to an epitope in Region I of mesothelin. Unfortunately, Region I contains the interaction site MUC16/CA125, a mesothelin-interacting protein that is present in the serum of patients with mesothelin-related cancers. Because the current therapeutic mAb candidates must compete with MUC16/CA125 for binding to mesothelin, they may not reach their full therapeutic potential due to interference. NIH inventors generated several rabbit mAbs that recognize unique epitopes of mesothelin: (1)...
Summary: NCI seeks proposals from parties interested in licensing an improved method for the identification of TCRs from bulk populations of TIL for the development of cancer immunotherapies. Description of Technology: One form of adoptive T cell therapy (ACT) consists of harvesting tumor infiltrating lymphocytes (TIL), screening and isolating TIL which display tumor antigen-specific T-cell receptors (TCR), expanding the isolated T cells in vitro, and reinfusing them into the patient for treatment. While highly active in the treatment of certain cancers (e.g., melanoma), current methods used to produce cancer-reactive T cells require significant time and may not adequately identify the desired TCRs which bind cancer targets. Researchers at the National Cancer Institute (NCI) Surgery Branch have developed a method which allows for the identification of TCRs from bulk populations of TIL. This method generates induced pluripotent stem...
Mosquito-transmitted dengue virus is one of the leading causes of illness in the tropics and subtropics. There is currently no vaccine available and a number of DENV diagnostic and research applications depend on the production of large amounts of these viruses. However, due to the slow growing nature of DENVs these protocols are very time-consuming. Researchers at the CDC have engineered stable, rapidly growing dengue-like viruses by combining the fast replicative ability of the West Nile virus with the immunogenic premembrane and envelope surface proteins of DENV serotypes 1, 2, 3, and 4, respectively. These DENV structural features are involved in a number of biological functions including virus-cell attachment and initiation of virus-specific antibody production. In turn, the chimeric viruses are more infectious and virulent than wild type DENV, but they do respond similarly in neutralization assays. The investigators also...
Enhancing the biocompatibility and potency of lipid nanoparticles (LNPs) by refining the structure of ionizable lipids through an iterative method. Problem: Ionizable lipids play a crucial role in determining the potency and biocompatibility of LNPs. Current approaches, medicinal chemistry, and combinatorial chemistry, each have limitations. Medicinal chemistry is laborious and low throughput, while combinatorial chemistry often fails to produce lipids that are both potent and biocompatible. Solution: The innovative approach combines the strengths of medicinal and combinatorial chemistry, resulting in a highly efficient method that generates potent and biocompatible lipids, termed "UPenn Lipids." Many of these lipids surpass the performance of currently approved ionizable lipids. Inventors: Xuexiang Han, Michael Mitchell, Rohan Palanki.
This technology includes an efficient lentiviral vector-based method for gene transfer into NK cells and demonstrates a stable and long-term robust expression of transgenes for the treatment of cancer. High gene transfer rates into primary cells being transduced and the ability to produce high titers of virus particles for large-scale transduction of patient cells are prerequisites for clinical trials. Lentiviral vectors can be produced in high titer and concentrated without compromising their transduction efficiency. Additionally, the described method is cheaper and simpler to apply clinically as it does not require the need for several cumbersome and expensive. The present invention of a highly efficient lentiviral vector-based gene transfer protocol can be used to complement a number of already optimized ex vivo NK cell expansion protocols to generate large numbers of genetically reprogrammed NK cells potentially revolutionizing NK...
Available for licensing are inhibitors that target the USP1/ UAF1 deubiquitinating enzyme (DUB) complex. The FDA approval and commercial success of Velcade®, a small molecule proteasome inhibitor, has established the ubiquitin-proteasome system (UPS) as a valid target for anticancer treatment. However, proteasome inhibitors in general suffer from a narrow therapeutic index and acquired resistance. A promising alternative to proteasome inhibition has been to target the enzymes upstream of proteasome-mediated protein degradation, i.e. the ubiquitin conjugation and deconjugation, to generate more specific, less toxic therapeutic agents. The investigators have developed small molecules that target the USP1/ UAF1 DUB complex that acts upstream of UPS and has been implicated in the DNA damage response. These compounds are the most potent and selective DUB inhibitors reported to date. Moreover, the inhibitors act synergistically with...
This technology is a highly sensitive tethered-bead immune sandwich assay. Analyte molecules are captured between two antibodies, a capture antibody and a detection antibody. The capture antibody on a micron-size bead binds analyte from a sample fluid. The bead-captured analyte is then exposed to a “detection” antibody that binds to the bead-captured analyte, forming a “sandwich”. The sandwiched analyte-bead complex then connects to a flexible polymer (such as DNA) anchored on a solid surface to form tethered particles. Binding the analyte-bead complex to a flexible polymer forms tethered particles and may be done, for example, by streptavidin biotin. Motion of the tethered beads easily identifies bound analyte. The tethered beads are quantified using low-magnification light microscopy. Prior enhanced sensitivity tethered bead technologies require expensive and cumbersome detection equipment. This assay is inherently single molecule,...
The tumor-suppressor p53 protein plays a major role in tumor development. Most human cancers fail to normally activate wild-type p53, which is at least partly responsible for the unregulated growth of cancer cells and their failure to undergo apoptosis. While many chemotherapeutics enhance p53 levels, their non-specific DNA damage (genotoxicity) causes unfavorable side effects. Defects in the pathways that control the stabilization and activation of p53 in response to stress can contribute to cancer development, without the requirement for mutation within the p53 gene itself. Many tumors that retain wild-type p53 show evidence of alterations that prevent efficient activation of p53 in response to stress, linked to a failure to inactivate HDM2. In these tumors, inhibition of HDM2 and reactivation of p53 is an attractive therapeutic strategy. Researchers at the National Cancer Institute (NCI) have developed a water-soluble, small...
HDAC and DNMT Inhibitors such as Trichostatin A (TSA) and 5-aza-cytidine are preventative therapies and reduce myocardial infarct volume following cardiac events Applications: Small molecule therapeutics that prevent ischemic injury and reverse myocardial infarction effects Inventors: Ibrahim Abdullah, Jonathan Epstein, Peter Gruber.
No effective therapeutics or vaccines against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) are available. The human-to-human aspect of transmission and the high mortality rate associated with MERS-CoV infection have raised concerns over the potential for a future MERS-CoV pandemic and emphasized the need for development of effective therapeutics and vaccines. The MERS-CoV-S protein is believed to be required for binding and virus entry during MERS-CoV infection. The antibodies of this technology represent candidate antibody-based therapeutics for treatment of MERS-CoV infection. Researchers at the NCI have developed human antibodies that target MERS-CoV. Certain of these antibodies bind with epitopes of the MERS-CoV receptor binding domain (RBD) of MERS-CoV spike (S) protein with high affinity and are capable of neutralizing the virus as demonstrated in a pseudovirus assay. Competitive Advantages: No vaccine or other...
Technology allowing efficient formation, delivery, isolation, and enrichment of single-copy Human Artificial Chromosome (HAC) for use in research, plant production, gene and cell therapy and more. Problem: Existing gene-editing techniques have limitations due to their reliance on viruses for delivery, restricting their packaging capacities. A more potent approach, HACs, can carry larger gene payloads alongside natural chromosomes without altering native genomes. However, a quarter century after the first human artificial chromosomes (HACs) were developed uncontrolled multimerization and DNA rearrangement still hinder their use. Solution: The inventors devised a method to produce HACs to create functional centromeres and engineered single-copy HACs allowing them to bypass the multimerization process. Furthermore, the inventors developed methodologies to deliver, isolate, and enrich these single-copy HACs, providing additional...
This invention relates to methods of rapidly detecting influenza, including differentiating between type and subtype. Unlike culture and serological tests requiring 5 to 14 days for completion, CDC researchers developed a rapid, accurate assay, which is easily adapted to kit form. This assay also requires less labor input than immunoassays. These methods can be used to quickly identify a broad variety of influenza types and subtypes, including viruses that may be involved in pandemics (such as H5N1, for example). Commercial applications: Influenza diagnostic using clinical specimens. High-throughput screenings. Influenza surveillance programs. Competitive advantages: Already FDA approved. Especially useful for H5N1 screening. Sensitive detection. Specific discrimination of influenza subtypes. Easily formatted as kit or array. Faster than culturing and serological identification methods. Less laborious and more objective than...
This invention relates to methods of rapidly detecting influenza, including differentiating between type and subtype. CDC researchers have developed a rapid, accurate, real-time RT-PCR assay that has several advantages over culture and serological tests, which require 5 to 14 days for completion; this assay can also be easily implemented in kit form. To date, hundreds of human cases of infection with the H3N2 variant virus have been confirmed. The increased numbers of human infection of H3N2 variant virus has led to a need for a highly sensitive and specific assay for the diagnosis and confirmation of the H3N2 variant virus. Commercial applications: Influenza diagnostic using clinical specimens. High-throughput sample screening. Government, regional influenza surveillance programs. Competitive advantages: Especially useful for H3N2 screening. Sensitive detection. Specific discrimination of influenza subtypes. Easily formatted as kit...
The National Cancer Institute's Cancer and Inflammation Program is seeking statements of capability or interest from parties interested in licensing this technology. The type 1 insulin-like growth factor (IGF) receptor (IGF1R) is over-expressed by many tumors and mediates proliferation, motility, and protection from apoptosis. Agents that inhibit IGF1R expression or function can potentially block tumor growth and metastasis. Its major ligands, IGF-I, and IGF-II are over-expressed by multiple tumor types. Previous studies indicate that inhibition of IGF-I, and/or IGF-II binding to its cognizant receptor negatively modulates signal transduction through the IGF pathway and concomitant cell proliferation and growth. Therefore, use of humanized or fully human antibodies against IGFs represents a valid approach to inhibit tumor growth. The present invention discloses the identification and characterization of a fully human monoclonal...
Neuroblastoma is a rare pediatric cancer that affects one in every hundred thousand children under the age of fifteen in the United States. Current standards of care are chemotherapy and surgery, followed by stem-cell treatments, radiation and anti-ganglioside antibody therapy, which yield an average three-year survival rate of 10-45%. This demonstrates a need for more effective therapies. Glypican-2 (GPC2) is a cell surface protein that has been shown to be preferentially expressed on numerous pediatric cancers, including neuroblastoma. Due to this preferential expression, GPC2 represents a potential candidate for targeted therapy. Researchers at the National Cancer Institute’s Laboratory of Molecular Biology (NCI LMB) have developed and isolated several single domain monoclonal human antibodies against GPC2. This technology covers the naked GPC2 antibodies as well as their use as targeting domains in recombinant immunotoxins (RITs)...
249 million people were afflicted with malaria in 2022. There are five Plasmodium parasite species that cause malaria in humans. Of the five, Plasmodium falciparum causes most of the incidence of human disease. Most advanced malaria vaccine candidates can confer only partial, short-term protection in malaria-endemic areas. The pathogenesis of malaria is associated with blood-stage infection and antibodies specific to the parasite blood-stage antigens may be able to control parasitemia. To address this public health need, NIAID inventors have developed 35 human monoclonal antibodies that target the RH5 complex of blood-stage Plasmodium falciparum and were found to have potent activity in in vitro growth inhibition assays. Commercial applications: Method of prophylactic and/or therapeutic treatment by targeting blood-stage antigens of Plasmodium.. Competitive advantages: Most other commercially available antibodies targeting against...
Human anti-ADAMTS13 antibodies cloned from patients with acquired thrombotic thromobocytopenia purpura (TTP) for use in targeted therapies, and generation of animal models that recapitulate pathologic features of TPP. Applications: Development of more effective, targeted therapies for TTP, such as anti-idiotypic agents Generation of improved animal models of TTP that permits testing of therapeutics targeting human antibody/ADAMTS13 interaction Inventors: Eric Ostertag, Donald Siegel, X. Long Zheng.
A retrovirus can be any of a group of RNA viruses (i.e., HIV) that insert a DNA copy of their genome into the host cell in order to replicate. Retroviruses can cause persistent and often lifelong infections. As a result of a voluntary study of nonhuman primate workers in zoos and primate centers, CDC scientists have isolated a retrovirus (spumavirus) from an individual that had a rare occupational exposure to an infected chimpanzee. The isolated virus is genetically and antigenically similar to the strain from the infected chimpanzee but distinct from other human spumaviruses. This discovery has potential in various research and commercial applications. It can be provided as a research tool for screening spumavirus infections or used as a reagent in pathogenicity studies. Being a retrovirus, this discovery can be used as a vector for gene therapy or a recombinant virus vaccine. Finally, sera have been generated against this retrovirus...
This invention relates to rotavirus vaccine compositions and methods of vaccination. Rotaviral infection is the most commonly occurring gastrointestinal illness of children world, affecting both developed and developing economies. Additionally, rotavirus infections can affect livestock (especially calves and piglets), and resulting mortality/morbidity cause major economic losses for farmers and nations each year. The vaccine strains include Rotavirus A CDC-9 (P[4]Gl) and CDC-66 (P[4]G2 serotype). These strains represent common rotavirus serotypes and may serve as improvements or alternatives to current live, oral rotavirus vaccine strains. Further, this technology has demonstrated efficacy in a large animal (piglets) modeling. Commercial applications: Novel rotavirus vaccines. Neonatal/childhood vaccination initiatives. Rotavirus surveillance programs, important for both developing and developed nations. Competitive advantages:...
The complexity of taste discrimination (salty, sour, sweet, umami and bitter) varies between human individuals and populations. Sweet and umami (the taste of glutamate) tastes play a major role in the perception of calorically-rich and essential nutrients and there are well-documented differences in individual perception of sweet and umami flavorings, many of which appear to be genetic in origin. Studies of individuals within and between populations that vary in any of the taste receptors should be of direct interest to the multi-billion dollar food and flavoring industry as the characterization of such variants could be used to aid in the development of a variety of taste improvements in foods and orally administered medications. NIH researchers previously characterized bitter taste receptor variants in world wide populations [Human Mutation 26, 199-204; HHS Ref. No. E-222-2003/0] and have now extended their studies to the sweet and...
T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins. When a TCR is stimulated by an antigen, such as a tumor antigen, some signaling pathways activated in the cell lead to the production of cytokines, which mediate the immune response. There are ten (10) known members of the synovial sarcoma breakpoint X (SSX) protein family designated SSX-1 through SSX-10. The T cell receptors (TCRs) developed by these NCI scientists have specificity for SSX-2 and deliver a robust immune response when they encounter SSX-2 expressing cells. However, these TCRs also recognize five (5) other SSX family members,...
Summary: Researchers at the NCI seek research and co-development partners and/or licensing for the development of human monoclonal antibodies and antibody-based therapeutics against CD22. Description of Technology: CD22 is a common cell surface glycoprotein expressed in B-cells and present in B-cell lymphomas; e.g., hairy cell leukemia (HCL), non-Hodgkins lymphoma (NHL), chronic lymphoblastic leukemia (CLL), and other cancers. It is therefore a target for cancer immunotherapy. Conjugation of anti-CD22 monoclonal antibodies with toxins or drugs has shown promise in clinical trials. However, all monoclonal anti-CD22 antibodies used in clinical trials are of murine origin. This is problematic because they have the potential of causing immunogenic reactions when used repeatedly in patients to achieve higher efficacy. NCI scientists isolated two human monoclonal anti-CD22 Fab antibodies; m972 and m971 with 2nM and 20nM affinities...
Summary: The NCI seeks research co-development partners or licensees for monoclonal antibodies that specifically target cancer-expressed EGFR. Description of Technology: Epidermal growth factor receptor (EGFR) is a well-known oncogenic driver in lung cancer, head and neck cancer, glioblastoma multiforme (GBM) and other cancers. NCI inventors have previously isolated a mouse monoclonal antibody that binds to the human EGFRvIII – but not wildtype EGFR known as the 40H3 antibody (NCI Ref: E-103-2019). To improve the 40H3 antibody’s suitability for the clinic, the inventors humanized the antibody through the generation of multiple variants with distinct sequences. The inventors produced about 14 humanized candidates of the 40H3 antibody. Significantly, CAR Ts using one of the antibodies (A10) showed potent killing of cancer cells in various pre-clinical models overexpressing EGFR. The pre-clinical results obtained to date suggest that the...
Japanese encephalitis virus (JEV) is the prototype virus of the Japanese encephalitis (JE) group belonging to the Flavivirus genus of the Flaviviridae family. Other members of the group include Kunjin virus, St. Louis encephalitis virus, and West Nile encephalitis virus (WNV). JEV is widely distributed in South Asia, Southeast Asia, and the Asian Pacific Rim. In recent years, JE epidemics have spread to previously unaffected areas, such as northern Australia, Pakistan, India and Indonesia. The JE outbreak in India during July to November of 2005 was the longest and most severe in recent years, affecting more than 5,000 persons and causing more than 1,000 deaths. It is estimated that JEV causes 35,000 to 50,000 cases of encephalitis, including 10,000 deaths and as many neurologic sequelae, each year. The wide geographical distribution and the existence of multiple strains, coupled with the high rate of mortality and residual...
Immunoglobulins play a key role in the immune system. CDC has developed and tested hybridoma cell lines (monoclonal antibody (mAb) clones) for human IgG and other immunoglobulins. The mAbs generated from those hybridomas could be used as a reagent (second Ab) of anti-human immunoglobins in a diagnostic assay for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19 (coronavirus disease 2019) and other assays that detect antigen specific antibodies from human sera. Collaborating international scientists evaluated the mAbs which showed reactivity and specificity for human IgG (11), the IgG subclasses (59), or Gm allotypes (4) by employing different assay techniques or protocols. These mAbs that can be satisfactorily applied in several diagnostic testing methodologies such as enzyme-linked immunosorbent assay (ELISA), immunofluorescence microscopy, direct hemagglutination and hemagglutination...
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma and consists of three subtypes: activated B-cell (ABC), germinal center B-cell (GBC), and primary mediastinal B-cell (PMB). Despite advances in the front-line therapy for DLBCL, approximately one-third of patients will relapse. Substantially worse outcomes have been reported for patients diagnosed with ABC DLBCL and treated with standard chemoimmunotherapy, suggesting the need for novel strategies that improve treatment outcomes. ABC DLBCL cell survival depends largely upon NF-κB signaling being constitutively active. The linear ubiquitin chain assembly complex (LUBAC) participates in NF-κB signaling, consists of three proteins (HOIP, HOIL-1L, and SHARPIN), and protects against apoptosis. Inhibiting LUBAC using HOIP and/or SHARPIN peptide inhibitors attenuates LUBAC activity and promotes ABC DLBCL cell death. LUBAC peptide inhibitors present a new...
Technology Overview: This invention relates to a novel discovery on the use of cholesterol lowering agents to treat tendon injuries. Based on clinical and basic research, the Penn inventors have demonstrated that hyperlipidemia has deleterious effects on the overall structure and function of tendons rendering them more susceptible to injury and... Inventors: Joseph Abboud, Louis Soslowsky.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children with approximately 3,250 new cases occurring per year in the United States. About 20% of cases are refractory to current treatment protocols and there is a desperate need for targeted therapies that do not result in adverse side effects such as cognitive impairment. The Interleukin-7 receptor-α (IL-7Rα) was identified as a major pathway driving T-cell derived ALL (T-ALL). Researchers at the National Cancer Institute (NCI) developed antibodies selectively targeting IL-7Rα. Two lead antibody candidates, designated 4A10 and 2B8, selectively bind IL-7Rα with nanomolar affinity. Each lead antibody mediates leukemic cell killing by antibody-dependent cellular cytotoxicity (ADCC) and causes a significant reduction in T-ALL cell burden when administered in a xenograft mouse model harboring patient derived leukemia. Tumor reduction occurred despite the absence of ADCC...
Summary: The National Cancer Institute (NCI) seeks co-development partners and licensees for a human cytotoxic T lymphocyte agonist epitope from the C-terminal subunit of mucin 1 (MUC1-C), which can be used as a peptide, polypeptide (protein), in a cancer vaccine or T-cell targeted therapy to target many tumor types. Description of Technology: Many human carcinomas and hematologic malignancies overexpress mucin 1 (MUC1), a transmembrane glycoprotein composed of heterodimers formed by a large, N-terminal subunit (MUC1-N) and a smaller, C-terminal subunit (MUC1-C). In tumors, the MUC-1 heterodimer becomes abnormally hypoglycosylated – leading to the exposure of antigenic epitopes to the immune system. Aberrant MUC1 expression, and in particular its MUC1-C subunit, has been associated with poor prognosis and correlates with cancer metastasis – further establishing MUC1 as a target for cancer therapy. Inventors at the National Cancer...
This technology includes the identification and use of niclosamide analogs and prodrugs for the treatment of SARS-CoV-2 infection. In-vitro studies have found niclosamide, an old anthelminthic drug, to be potent and effective against Covid-19. But the broad antiviral effect of niclosamide is offset by the low solubility of the drug, leading to poor oral absorption. The niclosamide analogs and prodrugs included in this technology have better in vitro physicochemical properties. Also, these analogs were comparable to niclosamide in the in-vitro 3D models of SARS-CoV-2 infection. Pharmacokinetic studies of a prodrug conducted in mice and hamsters has shown better absorbtion of the active niclosamide, with higher concentrations of niclosamide in both plasma and lungs (the primary site of COVID-19 disease manifestation). The oral bio-availability of niclosamide is greatly enhanced with this prodrug. Commercial applications: Further...
Available for licensing and commercial development are novel biotechnological tools, prophylactics, therapeutics, and methods for modulating the activation state of an antigen presenting cell (APC) and thereby modulating the activation of a killer T cell. The activation of a killer T cell can occur in a two cell complex and two sequential steps: a) in the first step, an APC stimulates a T helper T cell, which in turn stimulates or "superactivates" the APC to differentiate to a state where it can independently stimulate a killer T cell; b) in the second step, the APC encounters the killer T cell and stimulates it so that killer T cell priming is achieved in a helper independent fashion. The first step can be bypassed altogether by viral infection or an interaction with certain molecules at the cell surface of APCs, such as CD40. More specifically, the invention consists of a method of identifying a ligand as a candidate for...
AAV vectors offer unique advantages in gene therapy applications. Studies have shown that these replication deficient parvovirus vectors can deliver DNA to specific tissues and confer long-term transgene expression in a variety of systems. Although many studies have looked at the tissue-specific expression elicited by each of the AAV serotypes, a true understanding of how AAV transduces these tissues is still unclear. Of the large AAV family, only a few receptors or co-receptors have been identified. The ability to better target transduction to specific tissues on the basis of the receptors that each serotype uses for entry is essential for selecting a serotype given the receptor expression in specific tissue, or to exploit altered receptor expression under disease conditions. AAV6 has been reported to effectively transduce muscle, lung, brain, and multiple types of tumors, including gliomas and lung adenocarcinomas. By using a...
Description of Technology: Pancreatic cancer is the fourth most common cause of cancer deaths in the U.S. The overall 5-year survival rate is 8.5%. Glypican-1 (GPC1) is a cell surface heparan sulfate proteoglycan protein overexpressed in pancreatic cancer. Due to preferential expression, GPC1 represents a potential candidate for targeted therapy for pancreatic cancer and other GPC1-expressing cancers, such as prostate. Researchers at National Cancer Institute (NCI) developed novel Chimeric Antigen Receptors (CARs) specific for GPC1 that include short Immunoglobulin subclass 4 (IgG4) hinge sequences between the extracellular antigen recognition domain and the transmembrane domain. Hinge changes in CAR design can achieve the threshold of antigen density required for optimal CAR-T cell activity. Significantly, the optimized GPC1-IgG4 hinge CARs have shown rapid and complete tumor regression in mouse models. Potential Commercial...
Summary: Researchers at the NCI seek licensing and/or co-development research collaborations for developing new nanobody-based CAR and/or antibody-T-cell receptor therapies for treating liver cancer. Description of Technology: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Globally, HCC is the sixth most prevalent cancer and third leading cause of cancer-related morbidity. Standard treatment for HCC is not suitable for a large proportion of liver cancer patients. Part of this is because less than a quarter of HCC patients are surgical candidates for curative-intent treatment. As a result, alternative treatments are needed. Chimeric antigen receptor (CAR) T cell therapy is a promising alternative approach selectively targets targeting tumors via tumor-specific antigens. However, to date, no effective CAR T cell therapy exists for HCC. Researchers at National Cancer Institute (NCI) developed novel Chimeric...
Researchers developed an LNP-mRNA-based vaccine that encodes different cytokine mRNAs, as a method to enhance CD8+ T cell responses and memory formation. Problem: Lipid nanoparticles (LNPs) are an emerging technique to deliver mRNA in vivo more efficiently. While recent progress in mRNA technology has allowed the rapid development of SARS-COV2 vaccines, these protective responses often require high doses and boosting to generate long lived protective T cell responses. Solution: Dr. Hunter and his team have developed a method to promote T-cell immune responses to vaccines, by delivering mRNA that encodes cytokine (IL-12 or IL-27) concurrently with the antigen encoding mRNA. With this approach, they enable the future development of new vaccines by “mixing and matching” target antigens with different cytokines to enhance the memory T cell pool. Inventors: Mohamad-Gabriel Alameh, Emily Aunins, Christopher Hunter, Anthony Phan.
Melanoma is a particularly aggressive form of cancer primarily caused by over-exposure to sunlight. Although melanoma can strike at any age, the malignancy disproportionately impacts persons of advanced age, as these individuals often have decades of repeated exposure to harmful levels of ultraviolet radiation. Scientists at NIH among others have clarified the link between advanced melanoma and other malignancies and expression of SPANX-B. Researchers at the National Institutes of Health (NIH) characterized this novel tumor-associated antigen, SPANX-B, as naturally immunogenic and expressed in a variety of human malignancies, including melanoma and lung, colon, renal, ovarian and breast carcinomas. In melanoma specifically, SPANX-B expression associates with advanced and metastatic disease. Moreover, the researchers found several agonist epitope peptides from SPANX-B that can be used to activate the immune system to eradicate tumors...
This technology includes a novel vaccine for forming autoantibodies against apoC-III, a plasma enzyme that inhibits lipolysis. The vaccine can possibly be used to treat patients with high triglycerides and are at risk for pancreatitis and cardiovascular disease. This disclosure describes an ApoC3 immunogen that includes an antigenicApoC3 peptide linked to a bacteriophage virus-like-particle (VLP) immunogenic carrier. Commercial applications: This vaccine has significant potential for further development as a potential therapeutic for hypertriglyceridemia. Competitive advantages: This technology for inducing autoantibodies against endogenous ApoC3 using peptides conjugated to virus-like-particles (VLPs) is completely novel and if successful would be a much lower cost than using antisense oligonucleotides and likely could be more widely used. Source institute: NHLBI. Inventors: Remaley, Alan.
A first-in-class small-molecule strategy designed to convert immunologically “cold” pancreatic tumors into immune-responsive tumors by activating endogenous inflammatory signaling.
Immunotoxin chimeras of DNaseI and cytolethal distending toxin (CdtB subunit) are an effective therapeutic against epithelial tumors. Inventors: Joseph Dirienzo.
The invention concerns immunotoxins and methods of using the immunotoxins for the treatment of autoimmune diseases and T cell malignancies. The immunotoxins are targeted via an antibody that is specific to T cells. This allows the specific ablation of malignant T cells and resting T cells. The transient ablation of resting T cells can "reset" the immune system by accentuating tolerizing responses. The toxin portion of the immunotoxin is genetically engineered to maintain bioactivity when recombinantly produced in Pichia pastoris . Data are available in transgenic animals expressing human CD3epsilon which supports the effects of the immunotoxin against T cells. Commercial applications: Treatment of autoimmune diseases such as multiple sclerosis, lupus, type I diabetes, aplastic anemia. Treatment of T cell leukemias and lymphomas such as cutaneous T cell leukemia/lymphoma (CTCL). Competitive advantages: Specificity of the immunotoxin...
CDC researchers have developed a novel acoustic whole body plethysmograph (AWBP) that allows measurement of tidal volume in lab animals, independent of gas compression in the lung. This system provides particular advantages over the traditional whole body plethysmograph (WBP) when measuring model animals with increased gas compression due to increased airway resistance or increased acceleration in the breathing pattern. Measurement of tidal volume in conscious, unrestrained mice has traditionally been performed using WBP. An animal is placed in a chamber where pressure changes due to respiration are observed, which are then related to tidal volume. Although the effects of gas compression on the WBP signal of normal mice may be negligible, gas compression in mice with altered breathing pattern and/or increased airway resistance can produce significant errors in the measurement of tidal volume. A major advantage of this novel AWBP...
InflammationOphthalmologyOncologyInfectious DiseaseImmunologyCardiometabolicBiologicDiagnostic / BiomarkerAI / ML
CDC researchers have improved upon a prior, HHS patented mass spectrometry-based Endopep-MS assay that is able to rapidly detect and differentiate all seven botulinum neurotoxin (BoNT) types A to G. This current improvement comprises the addition of two optimized substrate peptides that increases the assay's sensitivity,relative to prior substrates, for botulinum neurotoxin type-E (BoNT/E) by greater than 100 fold. Currently, the primary method of detecting BoNT contamination entails mouse lethality bioassays. In addition to the sacrifice of numerous animals, these lethality assays are expensive and require several days to obtain results. During a suspected BoNT exposure, time is of the essence. The previously patented mass spectrometry approach can provide diagnostic results for all seven BoNT types in a matter of hours, at greater cost-efficiency and without animal toxicity studies. The specific innovation builds upon those earlier...
Targeting the CD22 receptor of B-cells with chimeric antigen receptor (CAR)-T cells has been a promising new therapy to treat B-cell malignancies in clinical trials, inducing remission in 70% of patients with relapsed acute lymphoblastic leukemia (ALL). However, diminished CD22 expression on B-cell surface can lead to relapse and decreased remission duration, which may be prevented through increasing CAR-T affinity towards CD22. Researchers at the National Cancer Institute (NCI) developed an affinity-matured monoclonal antibody panel including an anti-CD22 antibody variant, L7, displaying a higher affinity against CD22 than the non-affinity matured versions. The inventors at the NCI developed CAR-T cells incorporating the L7 variable fragment and observed prolonged remission using the L7-CAR-T treatment in combination with Bryostatin1-induced CD22 expression in vivo. The L7 antibody can also be used in other antibody-based...
Summary: NICHD is seeking licensees for development of an adeno-associated viral (AAV) vectors for the treatment of glycogen storage disease type Ia (GSD-Ia). Description of Technology: GSD-Ia is an inherited disorder of metabolism associated with life-threatening hypoglycemia, hepatic malignancy, and renal failure caused by the deficiency of glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC). Current therapy, which primarily consists of dietary modification, fails to prevent long-term complications in many patients, including growth failure, gout, pulmonary hypertension, renal dysfunction, osteoporosis, and hepatocellular adenomas (HCA). Gene therapy-based techniques, which directly address the underlying genetic deficiency driving the disorder, offer the prospect of long-term remission in patients with GSD-Ia. Researchers at the NIH National Institute for Child Health and Human Development developed adeno-associated viral (AAV)...
Researchers at the National Cancer Institute (NCI) have developed a new method of improving the efficacy of vaccines in patients with human immunodeficiency virus (HIV) by activating Ras. This method can be used to develop more efficacious vaccine compositions by activating Ras before, during, or after vaccination. Additionally, the researchers discovered that modulation of the Ras pathways could be a predictive biomarker of protection against HIV. This novel method has been shown to effectively stimulate the Ras pathway and to improve vaccine protection from Simian Immunodeficiency Virus (SIV), a HIV animal model, in chimpanzees. More than 30 million people are currently infected with HIV worldwide and it is estimated to increase by as much as 3 million new infections yearly. Although effective anti-retroviral therapies exist, millions still succumb to acquired immune deficiency syndrome (AIDS) every year, underscoring the need to...
Novel high-affinity PARP inhibitors with various properties for imagining and treating cancer and inflammation-related diseases Applications: Cancer imagining, therapy, and radiotherapy Neuroimaging and neuroinflammation treatment Inventors: Robert Mach.
Targeted toxins (e.g., immunotoxins) are therapeutics that have at least two important components: (1) a toxin domain that is capable of killing cells and (2) a targeting domain that is capable of selectively localizing the toxic domain to only those cells which should be killed. By selecting a targeting domain that binds only to certain diseased cells (e.g., a cell which only expresses a cell surface receptor when in a diseased state), targeted toxins can kill the diseased cells while allowing healthy, essential cells to survive. As a result, patients receiving a targeted toxin are less likely to experience the deleterious side-effects associated with non-discriminate therapies such as chemotherapy or radiation therapy. A particular toxin that has been used in targeted toxins is Pseudomonas exotoxin A (PE). The effectiveness of PE-containing targeted toxins has been demonstrated against various forms of cancer, including hairy cell...
Scientists at NIH have identified a process to select highly tumor-reactive T cells from a patient tumor sample based on the expression of four specific T cell surface markers: programmed cell death protein 1 (PD-1; CD279), 4-1BB (CD137), T cell lg-and mucin-domain-containing molecule-3 (TIM-3), and/or lymphocyte activation gene 3 (LAG-3). After this enriched population of tumor fighting T cells, primarily tumor infiltrating lymphocytes (TIL), is selected and expanded to large quantities, it gets re-infused into the patient via an adoptive cell transfer (ACT) regimen. The key finding for this process is that the most tumor-reactive TIL found in a bulk population of cells obtained from a patient tumor sample reliably exhibit high expression of one or more of these four markers. By selecting cancer attacking TIL from a patient's tumor based on these markers prior to re-infusion, in vitro culture time is reduced to grow up the desired T...
In the last decade, prescription opioid abuse and misuse has been a major contributor to mortality in the United States, resulting in a serious national public health crisis. Nearly 12 million Americans used prescription opioids nonmedically in 2018, with >67,000 people dying from an opioid overdose. The federal response to the opioid crisis includes research support toward the development of non-addictive analgesics and additional medications to treat opioid use disorders (OUD). Recently, a novel series of (R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl) piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide (8)-(R)VK4-116 have been discovered as high affinity and selective D3R (Dopamine D3 receptor) lead molecules for the treatment of opioid use disorders (OUD) by a discovery team at NIDA (NIH). Furthering the earlier work by colleagues at NIDA, NCATS scientists have developed new synthetic routes to accelerate synthesis and yields...
Problem: A major challenge in drug delivery is ensuring that the drug reaches the target organ at a concentration sufficient to treat the disease. This is particularly problematic for acute illnesses of the vasculature, such as acute respiratory distress syndrome (ARDS), ischemic stroke, and myocardial infarction. In these diseases, patients are often... Problem: A major challenge in drug delivery is ensuring that the drug reaches the target organ at a concentration sufficient to treat the disease. This is particularly problematic for acute illnesses of the vasculature, such as acute respiratory distress syndrome (ARDS), ischemic stroke, and myocardial infarction. In these diseases, patients are often too sick to tolerate off-target drug side effects, and systemically delivered drugs rarely accumulate to a significant extent in the organs affected by pathology. Solution: Drs. Jacob Brenner and Vladimir Muzykantov have developed a drug...
RNA nanoparticles have the potential to serve as excellent drug or imaging delivery systems due to their designability and versatility. Furthermore, the RNA nanoparticles of the invention are also capable of self-assembly and potentially form nanotubes of various shapes which offer potentially broad uses in medical implants, gene therapy, nanocircuits, scaffolds and medical testing. This technology, which was co-invented by researchers at National Cancer Institute and the University of California at Santa Barbara (UCSB), describes the computational design of various RNA nanoparticles. These polyvalent nanoparticles utilize RNA motifs as building blocks that give the particles their unique characteristics. The motifs can be pre-defined and chosen to give the particles desired characteristics (e.g. size and shape) tailored for a variety of applications. The polyvalent particles can utilize multiple unique positions to carry functional...
The thymus is an integral part of the adaptive immune system as it generates T cells. Its function diminishes rapidly as the body ages, leading to a compromise of the immune system in the elderly. Reconstitution of adaptive immunity through mass production of different T cell types is therefore a therapeutic need in immunocompromised populations. Furthermore, production of T cells with specific receptors targeting cancer cells is an important cancer immunotherapy approach. However, current in vitro methods are not efficient in producing conventional CD4 or CD8 positive T cells, as they result in production of immature, CD4 and CD8 double positive T cells which are not useful for therapy. This problem may be solved through a three-dimensional cell culture system mimicking the human thymus. Researchers at the National Cancer Institute (NCI) have developed a novel approach to generate autologous thymic organoids from human pluripotent...
Patients receiving immunotoxin cancer therapy are less likely to experience the deleterious side-effects associated with non-discriminate therapies such as chemotherapy or radiation therapy. Unfortunately, the continued administration of immunotoxins often leads to a reduced patient response due to the formation of neutralizing antibodies against immunogenic epitopes contained within Pseudomonas exotoxin A (PE). To improve the therapeutic effectiveness of PE-based immunotoxins through multiple rounds of drug administration, NIH inventors have sought to identify and remove the human B cell epitopes within PE. Previous work demonstrated that the removal of the murine B cell and T cell epitopes from PE reduced the immunogenicity of PE and resulted in immunotoxins with improved therapeutic activity. This technology involves the identification and removal of major human B cell epitopes on PE by mutation or deletion. Considering these...
A method to manipulate tumor-associated macrophages by targeting the mitochondrial electron transport chain, improving the efficacy of immune checkpoint blockade cancer therapies. Problem: Many cancer therapeutics work by activating the immune system to attack a tumor. These drugs, known as immune checkpoint blockade (ICB) therapies, commonly fail because cancers develop resistance to ICB therapy. Prognosis is associated with tumor-associated macrophages (TAMs), which exist in pro-tumor and anti-tumor states. Pro-tumor TAMs help tumors recover from therapy by inhibiting immune responses and promoting angiogenesis, limiting ICP therapy efficacy. The ratio of pro-tumor to anti-tumor TAMs is a strong predictor of survival and ICB therapy efficacy, but no available therapies are available to shift the TAM population to an anti-tumor state. Solution: This technology addresses a crucial challenge in cancer treatment by regulating the...
Summary: The NCI is looking for innovative companies interested in co-developing and/or licensing a novel nucleic-based therapy based on the conditional activation strategy. Description of Technology: Gene therapy research has yielded FDA-approved treatments for an array of diseases. However, challenges facing nucleic-acid based therapeutics include non-specific delivery and degradation of the nanoparticles. NCI investigators have developed a solution to address these challenges in their novel nucleic-based therapy based on the conditional activation strategy. The inducible activation nucleic acid hybrid switch overcomes the drawbacks of current technologies through its unique design. The implementation of nucleic acid logic elements in these constructs circumvents off-target effects. The functional oligonucleotide constructs would only be generated and activated in environments denoted by the presence or absence of a specific cognate...
This technology described in this patent application relates the first reported infectious human parvovirus B19 clone, methods of cloning the parvovirus B19 genome as well as other viral genomes that have secondary DNA structures that are unstable in bacterial cells. The infectious clone and methods of producing the same would be useful in producing infectious virus, which can in turn be used, among other things, to identify and develop therapeutic agents for treatment and/or prevention of human parvovirus B19 infections. The infectious parvovirus B19 clone is also available for licensing. Additional information about this invention can be found in Virology 2004, 318(1), 142-152. Source institute: NHLBI. Inventors: Zhi, Ning.
Mechanistically-defined, localized, and repurposed immuno‑metabolic precision therapy that overcomes age‑related resistance to immune checkpoint and targeted therapies in non‑small cell lung cancer (NSCLC).
Adoptive Cell Therapy (ACT) is a promising technique that uses a patient's own T cells to treat cancer. The process requires removing and engineering a patient's T cells to express a chimeric antigen receptor (CAR) or T cell receptor (TCR) that targets a specific cancer antigen. When the modified T cells are reintroduced into the patient, the T cells attack and kill cancer cells that express the antigen, thereby treating the patient. Although ACT holds a great deal of promise, there are still technical drawbacks to be overcome, such as loss of anti-tumor activity due to T cell senescence. This invention addresses this technical drawback by using T cells that express the transcription factor c-Myb (or a functional variant thereof) at elevated levels as the host for transduction with CARs or TCRs. T cells that exhibit elevated expression of c-Myb display inhibited differentiation, allowing the cells to survive, proliferate and serve in...
Description of Technology: Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL), T cell receptor (TCR) and Chimeric Antigen Receptor (CAR) engineered T cells, or hematopoietic stem cell transplantation, is a promising new approach to cancer treatment. ACT harnesses an individual's adaptive immune system to fight against cancer, with fewer side-effects and more specific anti-tumor activity. Despite their promise of ACT as curative, these therapies are often limited by the persistence and robustness of the responses of the T cells to the cancer cells. Altering metabolic pathways is one way to affect the actions of T cells, and different cellular subtypes vary in how they produce and expend energy. T cell metabolism can be altered by several factors, including cytokine stimulation and by inhibiting lactate dehydrogenase (LDH), which mediates the final step in glycolytic metabolic pathway. Researchers at the National...
Differentiated and precise approach for selectively targeting pain receptors to treat different types of pain effectively and safely without use of opioids.
Disease-modifying therapy with differentiated mechanisms of action to restore memory and motor function in neurodegenerative diseases and neurodevelopmental disorders.
Proinflammatory T-helper 17 cells (Th17) play important roles in host immune defense against infection, but uncontrolled activation of these cells, known as the Th17 response, may cause autoimmune and autoinflammatory diseases (uveitis, multiple sclerosis, rheumatoid arthritis, and Crohn’s disease) through the effects of Th17 lineage cytokines (such as, IL-17F, IL-22 and GM-CSF). Importantly, IL-17A (a proinflammatory cytokine) represses other Th17 lineage cytokines by upregulating the regulatory cytokine IL-24. Loss of this regulatory pathway due to IL-17A neutralization, and consequent upregulation of the other Th17 cytokines, may result in reduced efficacy of anti-IL-17A therapy. The inventors suggest that targeting the Th17 lineage cytokines as a class, by augmenting IL-24 may be a better approach for controlling the Th17 response than targeting IL-17A alone, which is currently under development by pharmaceutical companies. For...
Summary: The National Eye Institute (NEI) seeks research co-development partners and/or licensees to advance the production and uses of interleukin-27 (IL-27) producing B-regulatory cell (i27-Breg) therapy for immune related autoimmune disorders. These disorders include but are not limited, to age-related macular degeneration (AMD), graft-versus-host disease (GVHD), multiple sclerosis (MS) and transplant rejection. Description of Technology: Autoimmune diseases in which the immune system attacks the body's own tissues or organs include: graft-vs-host disease (GVHD), age-related macular degeneration (AMD), multiple sclerosis (MS), uveitis and encephalomyelitis. These diseases can result in blindness, paralysis, and significant morbidity impacting quality of life. In GVHD, the allogeneic transplant views the recipient’s body as foreign, and the transplant attacks the body. Uveitis is comprised of a diverse group of potentially...
Enhancing exercise performance by modulating the activity of motivation-generating brain regions via stimulation of cannabinoid (CB1) receptors of the enteric nervous system. Problem: An increase in sedentary lifestyles driven by the modernization of society has led to a surge in several metabolic and neurological diseases worldwide. Although exercise is an essential and accessible method to reduce the risk of such illnesses, there is a general lack of motivation for exercising. Moreover, influencing motivation by pharmacologically engaging the brain directly has been impeded by the presence of the blood-brain barrier. Solution: Interoceptomimetics are dietary supplements that stimulate the activity of interoceptive circuits in the gut, which are neural circuits connecting the gut-innervating sensory system to the brain. These supplements alter activity in specific brain regions by stimulating the peripheral enteric neural network,...
Intranasal delivering of dantrolene nanoparticles could potentially be used to inhibit memory loss and reduce amyloid plaques in patients with Alzheimer's disease. Problem: Alzheimer’s disease (AD) is a devastating neurodegenerative disease. The deficit in the development of new drugs targeting the amyloid pathology over the past several decades warrants exploration of alternative pathways that could be the primary cause of AD cognitive dysfunction. Solution: Disruption of intracellular calcium homeostasis by over activation of ryanodine receptor (RYRs) and/or NMDA receptors contributes to synaptic dysfunction even before the appearance of amyloid and tau pathology and symptoms of cognitive dysfunction in AD. Dr. Wei at the University of Pennsylvania has evaluated dantrolene, a ryanodine receptor antagonist, as a potential treatment for treatment of AD. Intranasal administrating of dantrolene nanoparticles showed improved brain uptake...
This Intranasal Dry Powder Inhaler (DPI), developed with Creare, Inc., allows low-cost delivery of powder vaccines. Nasal delivery has numerous advantages compared to traditional injected vaccines, including: 1) safe, needle-less administration by minimally-trained staff or patient; 2) better protection due to mucosal and cross-protection; and 3) decreased biohazard waste. Further, dry powder aerosol vaccine delivery is superior to liquid aerosol delivery in a number of ways, including: 1) no dose reconstitution required; 2) highly thermostable and may not need cold chain storage; 3) costs less to store and transport; 4) improved efficacy through elimination of liquid spray nasal-dripping. This CDC-Creare invention is unique in that it is inexpensive and suitable for single-use applications, such as vaccination. It prevents the dose being deposited within the lower respiratory tract, improving safety. This delivery system has a broad...
Intranasal delivery is a simple, inexpensive and needle-free route for administration of vaccines and therapeutics. This intranasal delivery technology, developed with Creare LLC., includes low-cost, disposable drug cartridges (DDCs) that mate with a durable hand-held device. The rechargeable-battery-powered device transmits ultrasonic energy to the DDC to aerosolize the drug and is capable of performing for eight hours at 120 vaccinations per hour. Potential applications for this platform technology include intranasal vaccination (e.g. seasonal or pandemic influenza vaccines) and intranasal delivery of locally active (e.g. antihistamines, steroids) or systemically active (e.g. pain medications, sedatives) pharmaceuticals. The DDCs themselves offer two unique benefits. First, all components that contact the active agent or the patient may be easily disposed of, which reduces the risk of patient cross-contamination and minimizes...
Intranasal nasal dantrolene nanoparticles alone, or in combination with lithium, can provide protection against depression and dementia with minimal or no side effects. Problem: Major depression disorder (MDD) affects 350 million patients in the world and about 16% of the population in USA. In addition, up to 50% of Alzheimer’s disease (AD) patients suffer from depression while depression could be a risk factor for development of AD. Solution: Dantrolene and lithium are the FDA approved drugs for treatment of malignant hyperthermia and bipolar disease, respectively. Both compounds have considerable clinical information about their clinical use and safety. However, lithium has a narrow therapeutic window, rendering it vulnerable to some side effects/organ toxicity. Previously Dr. Wei had discovered that intranasal administration of dantrolene nanoparticles led to an increased retention in the brain and decreased blood concentrations as...
Summary: The National Cancer Institute (NCI) seeks licensees for the further development of a family of novel iodonium analogs as therapeutics for cancer and/or chronic inflammatory conditions. Description of Technology: Diverse human cancers like colorectal, pancreatic, ovarian, melanoma, and pre-cancers express NADPH oxidases (NOX) at high levels. Reactive oxygen species (ROS) produced from metabolic reactions catalyzed by NOX in tumors are essential to the tumor’s growth and play a key role in inflammation-related conditions. Though drugs that inhibit ROS production by NOX could be effective against a variety of human cancers and chronic inflammation-related conditions, these types of drugs are not widely available. Investigators in NCI’s Developmental Therapeutics Branch have discovered a family of novel analogs of diphenylene iodonium (DPI) and di-thienyl-iodonium (DTI) as inhibitors of NOX and other flavin dehydrogenases for the...
Lipid nanoparticles for selective mRNA delivery to the placenta to treat pre-eclampsia, FGR, and other pregnancy-related disorders. Problem: 3-8% of pregnant women experience pre-eclampsia, or insufficient blood flow to the placenta. In severe cases, this can cause fetal growth restriction (FGR), in which the developing fetus cannot receive adequate blood flow. The only curative option for pre-eclampsia and FGR is to deliver the fetus regardless of gestational age. Because of this, pre-eclampsia and FGR are the leading causes of premature and stillbirths. Several groups have developed gene therapies to try to address pre-eclampsia and FGR. However, these viral-based approaches have the potential for permanent off-target effects in other organs and must be delivered directly into the placenta via an invasive uterine injection. Solution: The inventors identified a lipid nanoparticle composition to deliver mRNA-based therapeutics to the...
Using Mannich reaction-based combinatorial libraries to identify ionizable lipids for low-immunogenic and high-efficiency mRNA delivery. Problem: Lipid nanoparticle (LNP)-based delivery systems for mRNA-based therapeutics have recently demonstrated their clinical success in applications such as ONPATTRO® and the Pfizer/BioNTech and Moderna COVID-19 vaccines. However, existing LNP-based delivery systems have intrinsic high immunogenicity, restricting the mRNA therapeutics' protein expression levels, durability, and broader applications (e.g., redosing). Solution: The inventors constructed a series of Mannich reaction-based combinatorial libraries and used high throughput in vitro and in vivo screenings to identify the top-performing ionizable lipid, C-a16. This antioxidant lipid effectively reduces cellular inflammatory responses, extends intracellular protein expression duration, and mitigates intracellular reactive oxygen species...
Researchers at NIH have developed islet beta cell M3 muscarinic acetylcholine receptor knockout mouse. The mice were generated by crossing floxed mouse M3 muscarinic acetylcholine receptor mice with mice in which Cre recombinase was controlled by the beta-cell specific rat insulin promoter (RIP-Cre mice). Commercial applications: Study of the physiological role of beta-cell M3 muscarinic receptors in the regulation of glucose homeostasis and insulin release in vivo. Competitive advantages: Allows for study of the role of the M3 receptors in the pancreas without whole body effects confounding the results. Source institute: NIDDK. Inventors: Wess, Jurgen.
Ixodes scapularis is a blood-sucking tick and the principal vector of Lyme disease, a spirochetal illness caused by Borrelia burgdorferi and now the most common vector-borne infection in the United States; more than 50,000 cases have been reported during the last ten years. The salivary gland of I. scapularis has a number of pharmacologically active molecules that help the tick to successfully feed on blood, such as inhibitors of complement system, in addition to coagulation and platelet aggregation inhibitors. This invention describes Ixolaris, a protein that inhibits the initiation of blood coagulation by inhibition of components of the extrinsic pathway. Accordingly, Ixolaris blocks Factor X activation by Factor VIIa/TissueFactor, it attenuates Factor Xa production by the prothrombinase, and inhibits fibrin formation in a diluted prothrombin time. Ixolaris is highly specific since it does not inhibit other serine proteases. Because...
Known methods for predicting weight loss fail to account for slowing of metabolism as weight is lost and therefore overestimate the degree of weight loss. While this limitation of the 3500 Calorie per pound rule has been known for some time, it was not clear how to dynamically account for the metabolic slowing. The invention provides a Java applet for modeling of human metabolism to improve the weight change predictions. The model has been validated using previously published human data and the model equations have been published. A web-based implementation of the published dynamic model has been created to allow users to perform simulations for planning weight loss interventions in adults and accounts for individual differences in metabolism and body composition. Values to the user include being able to see whether the target weight loss is realistic when the necessary caloric restriction, exercise and timeframe components are...
Synergistic combination of mechanoporation and lipid nanoparticle (LNP) based transfection for an efficient, non-viral method of gene transfer to generate CAR-T cell therapies. Problem: Chimeric antigen receptor (CAR)-T cell therapy has transformed cancer treatment by engineering patients' T cells to precisely target and eradicate cancer cells. Conventional methods of CAR-T production rely on lentiviral transduction to integrate CAR genes into target cells. However, viral-based transduction can cause adverse effects and provoke unwanted immune responses such as cytokine release syndrome. Non-viral methods of gene transfer are safer but are not as efficient and can produce high cytotoxicity. Solution: The inventors achieve efficient and non-lethal gene delivery through LNP + Squeeze, an microfluidic-based intracellular delivery platform that combines mechanoporation and LNP based transfection. The inventors found that inducing...
Problem: Hereditary tyrosinemia type 1 (HT1) is a genetic metabolic disease caused by the inability to break down tyrosine, an amino acid present in many meats, dairy products, fruits, and nuts. This disease can be fatal within the first few months of life and increases the risk of liver cancer. The current treatment involves a strict drug regimen and... Problem: Hereditary tyrosinemia type 1 (HT1) is a genetic metabolic disease caused by the inability to break down tyrosine, an amino acid present in many meats, dairy products, fruits, and nuts. This disease can be fatal within the first few months of life and increases the risk of liver cancer. The current treatment involves a strict drug regimen and dietary restrictions. Many people are unable to maintain this regimen and require a liver transplant. Therefore, patients need a lasting cure for HT1. Solution: Inventors developed a gene-editing method to restore tyrosine processing and...
Recombinant fusion bioPROTACs are combined with cationic delivery agents and lipid formulations to enable cytosolic entry and on-demand intracellular degradation of target proteins. Problem: Many endogenous proteins remain difficult to modulate with conventional drugs due to limited opportunities for effective small-molecule binding. Protein-degradation strategies can expand what is addressable, but recombinant degraders still face practical intracellular delivery barriers. Common delivery approaches can be complex, cytotoxic, or introduce delays before degradation occurs. Solution: This technology provides recombinant fusion proteins and compositions designed to promote cytoplasmic delivery and targeted intracellular protein degradation. The fusion proteins combine an E3 ubiquitin ligase domain with a small protein binding scaffold that targets a selected intracellular protein for degradation. The compositions include a cationic...
Use of Leucine Rich Repeat Kinase 2 (LRRK2) inhibitors for the treatment of Intestinal Bowel Disorders (IBD) is disclosed. IBD is a broad term that describes conditions with chronic or recurring immune response and inflammation of the gastrointestinal tract. Crohn's disease and ulcerative colitis, two common forms of idiopathic IBD, are chronic, relapsing inflammatory disorders of the gastrointestinal tract. LRRK2 is a kinase encoded by a gene that contains a non-coding polymorphism (SNP). LRRK2 has been associated with and is a risk factor for inflammatory bowel disease. NIH inventors have shown that human cells expressing this SNP have increased levels of LRRK2 and, correspondingly, mice with increased levels of LRRK2 exhibit more severe Dextran Sulfate colitis. In various studies of the role of LRRK2 in cell signaling, NIH inventors have shown that increased levels of LRRK2 lead to increased pro-inflammatory cytokine secretion....
This technology includes the use of LZK and DLK inhibitors to be used for the treatment of head and neck squamous cell carcinoma (HNSCC) or lung squamous cell carcinoma (LSCC). Specifically, we demonstrate that inhibitors that can be repurposed to target LZK suppresses LZK kinase-dependent stabilization of MYC and activation of the PI3K/AKT pathway. In vivo preclinical cell line xenograft mouse model demonstrates that targeting LZK will suppress tumor growth. We also demonstrate that several additional compounds potently inhibit LZK and could serve as new therapeutic modalities. Commercial applications: LZK inhibitors that serve as lead compounds could lead to new therapies for the treatment of LSCC and HNSCC and other cancers with amplified LZK that include prostate, ovarian and small cell lung cancer. Competitive advantages: We have discovered LZK as a novel therapeutic target in squamous cell carcinomas with amplified LZK; over 50%...
Summary: NICHD seeks co-development partners and/or licensees for the further development of methods to target the La protein for the regulation of osteoclast fusion and osteoclastogenesis. Description of Technology: Millions of patients in the United States are afflicted by a host of bone diseases caused by osteoclast (specialized calls arising from the macrophage/monocyte lineage) dysfunction. Diseases include Paget’s disease, osteoporosis, fibrous dysplasia and osteolytic bone metastasis. The current standard of care for these diseases uses broad-spectrum therapies that either coat the skeletal system or inhibit osteoclast development in an effort to modulate osteoclastogenesis. New therapies are needed that specifically target osteoclast fusion – allowing patients to forgo the off-target side effects caused by existing, broad-spectrum therapies. Researchers at the National Institute of Child Health and Human Development (NICHD)...
Summary: The National Institute of Child Health and Human Development (NICHD) seeks licensees and/or research co-development partners for the development of an injectable contraceptive for women with a pharmaceutical formulation containing levonorgestrel butanoate (LB), a steroidal progestin. Description of Technology: This invention is a potential subcutaneous or intramuscular progestin-only, injectable contraceptive for women. Forty-five percent (45%) of pregnancies in the United States are unintended. In this group, one-third of reproductive age women are obese – increasing the risk of diabetes, hypertension and venous thromboembolism (VTE). All these are conditions for which most hormonal methods are contraindicated. Thus, additional safe and effective injectable contraceptive options are needed. A subcutaneous formulation may be self-injected without the need of a skilled care provider or medical office visit. Levonorgestrel...
A new class of anisimide-functionalized lipids that enables targeted delivery of lipid nanoparticles (LNPs) to activated fibroblasts in the liver. Problem: Lipid nanoparticles (LNPs) have been successfully used in FDA-approved therapies to deliver messenger RNA (mRNA) and small interfering RNA (siRNA) . One of the biggest challenge in developing a successful RNA therapies is its targeted delivery. Typically, LNPs require targeting ligands to be coated onto their surface to enable targeted delivery after the lipid is made. This added step often complicates the fabrication process. Solution: Rather than functionalizing LNPs with targeting ligands post-fabrication, this technology incorporates targeting capabilities directly into the lipid component to create ligand-thethered LNPs. This creates an affinity to the notoriously hard-to-target activated fibroblasts in the liver responsible for the buildup of collagen. Inventors: Xuexiang...
Lung-targeting lipid nanoparticles allowing organ specific mRNA delivery for gene therapy applications. Problem: Gene therapy via mRNA delivery allows the rapid generation of therapeutics and vaccines for a wide range of applications. However, mRNA is especially vulnerable to degradation in the body, necessitating packaging within lipid nanoparticles. While these lipid nanoparticles protect mRNA and facilitate delivery, to date they act in a non-specific manner, entering cells regardless of therapeutic relevance. Solution: This library of lipids allows the production of lipid nanoparticles that specifically target the lungs. This allows lung-specific targeting of mRNA gene therapy, increasing the efficiency of gene delivery and improving therapeutic efficacy. Further, these lipid nanoparticles are readily biodegradable, ensuring they can be cleared from the body after delivering their mRNA payload. Inventors: Michael Mitchell, Lulu Xue.
West Nile virus (WNV) has recently emerged in the U.S. and is considered a significant emerging disease that has embedded itself over a considerable region of the U.S. WNV infections have been recorded in humans as well as in different animals. From 1999-2014, WNV killed 1,765 people in the U.S. and caused severe disease in more than 41,762 others. This project is part of NIAID's comprehensive emerging infectious disease program. The methods and compositions of this invention provide a means for prevention of WNV infection by immunization with attenuated, immunogenic viral vaccines against WNV. The invention involves a chimeric virus form comprising parts of WNV and Dengue virus. Construction of the hybrids and their properties are described in detail in multiple publications. The WNV chimeric vaccine does not target the central nervous system, which would be the case in an infection with wild type WNV. Importantly, two successful...
This CDC-developed technology describes an automated system for monitoring worker hazard exposures by recording data about where and when hazards occur in a workplace or other environment. This allows the hazards to be avoided and harmful exposures and risks reduced. This field-tested technology consists of an integrated, hand-held electronics instrument and software system that will precisely correlate multiple exposure levels with position coordinates of the user and features real-time data acquisition. Workers in many outdoor occupations move about frequently during a typical day of work. Certain workers, such as agricultural and construction workers, are particularly mobile. This exposure monitoring system combines geographical location with real-time sensors and outputs the information to a user-friendly interface. By linking worker location throughout the workday to exposure levels from real-time monitors, Local Positioning...
Cell/Gene TherapyBiologicDiagnostic / BiomarkerAI / ML
This technology includes a product for local delivery of alkaline phosphatase for the treatment of periodontal disease. Our laboratory has discovered that factors regulating phosphate metabolism and specifically the appropriate balance between phosphate (Pi) and pyrophosphate (PPi) at local sites are needed for formation (development), maintenance and regeneration of the tooth root surface (cementum), periodontal ligament (PDL) and surrounding alveolar bone, i.e., the periodontal apparatus. Furthermore, we have shown in alkaline phosphatase knock out mice that targeting alkaline phosphatase to mineralized tissues promotes formation and regeneration of the periodontal apparatus. Commercial applications: Product for use as a local delivery to treat periodontal disease, to form new bone at local sites in preparation for implants and other dental appliances and to treat peri-implantitis. Competitive advantages: Less difficulty in the...
The five Muscarinic Acetylcholine (ACh) receptors are G-protein coupled receptors (M1R-M5R). M3 muscarinic ACh receptors are present in the central nervous system and the periphery. M3R knockout mice are viable and fertile, and have no major morphological abnormalities. They have a lean phenotype due to a combination of reduced caloric intake and increased energy expenditure. Because of their lean phenotype, M3R knockout mice have improved glucose tolerance and increased insulin sensitivity. Pharmacological blockade of central M3Rs may be a novel strategy for the treatment of obesity and associated metabolic disorders. In the airway, vagally-mediated bronchoconstriction responses were abolished in M3R knockout mice in vivo, suggesting that M3R antagonists may be useful in the treatment of chronic obstructive pulmonary disease (COPD) and asthma. Studies with M3R knockout mice also have shown that the M3R is the major muscarinic...
This technology relates to compositions and methods for improving the growth characteristics of cells engineered to produce live viruses such as the Influenza virus. Featured is a method that uses the gene candidate, siat7e, or its expressed or inhibited products in Madin Darby Canine Kidney (MDCK) cells. The gene expression modulates anchorage-dependence of the cell line thereby allowing scale-up on bioreactor platforms without the use of microcarrier beads and reducing production costs. More specifically, this technology claims use of the methods embodied in the patent application for production of the Influenza viruses (human, avian and canine). Commercial applications: This technology may be used to improve the production of prophylactic compounds against the seasonal flu. Influenza viruses are traditionally isolated and propagated in chicken embryonated eggs. Egg-derived viruses are the source of Influenza vaccine preparation....
CDC researchers have developed a Madin-Darby Canine Kidney (MDCK) reporter cell line that is exceptionally permissive for influenza virus replication and provides a highly specific, sensitive approach for the simultaneous detection and isolation of influenza viruses. Simplified antibody neutralization assays and high-throughput antiviral drug screening can also be easily and efficiently implemented using this reporter system. Laboratories generally rely on embryonated chicken eggs or mammalian cell cultures for isolation and propagation of influenza viruses. This approach is hampered by the relatively long times required to obtain test results (5 to 7 days) and substantial requirements for specialized materials, equipment and specially trained technician labor. This CDC-generated reporter system for influenza A virus uses highly permissive MDCK cells expressing a luciferase-encoding amplicon controlled by canine RNA polymerase I...
Summary: The National Eye Institute (NEI) seeks research co-development partners and/or licensees for the development of an eyedrop formulation to deliver a series of peptides as a gene-agnostic approach to treating inherited retinal diseases. Description of Technology: Retinitis pigmentosa (RP) is one of the most common inherited retinal diseases (IRDs) that is estimated to affect 1 in 4,000 people in the United States and worldwide. Over 100,000 people in the US, and 1.5 million people worldwide suffer from RP. RP leads to progressive photoreceptor cell degeneration and ultimately vision loss, with more than 90 genes implicated in molecular pathways towards photoreceptor cell death. Due to this high heterogeneity, therapeutic approaches targeting specific genes generally benefit few patients, while for most forms of RP few or no medical options are available. Peptide drug development has made great progress recently thanks to new...
The MUC-1 tumor associated antigen has been shown to be overexpressed and/or underglycosylated in a wide range of human cancers. The C-terminus region of MUC-1 (MUC-1C) has been shown to be an oncogene and has been associated with a more aggressive phenotype in several different cancers. Scientists at NIH have identified 7 new agonist epitopes of the MUC-1 tumor associated antigen. Compared to their native epitope counterparts, peptides reflecting these agonist epitopes have been shown to enhance the generation of human tumor cells, which in turn have a greater ability to kill human tumor cells endogenously expressing the native MUC-1 epitope. The agonist epitopes span both the VNTR region of MUC-1 and the C-terminus region. The epitopes encompass 2 major MHC alleles reflecting the majority of the population. Along with the method of use, the technology encompasses the use of these agonist epitopes in peptide- and protein-based...
Tetracycline-responsive transcriptional activator driven by the liver-specific mouse major urinary protein promoter (MUP-tTA). The E. Coli tetracycline operon regulatory system was used to generate a liver-specific transcription activation system that was inhibited by tetracycline. The transcription activator was a fused protein consisting of a tetracycline repressor gene (tetR) that was only active in the presence of tetracycline and a herpes simplex virus protein (VP-16) transcription activating domain (Tet-Off). Transcription was induced only in the absence of tetracycline (Tet-Off). A liver-specific promoter such as the mouse major urinary protein (MUP) promoter determined that the tetracycline-regulated transcriptional activator (tTA) would be expressed specifically in liver. To study the effect of the transcription activator on a target gene (for example, beta-galactosidase, LacZ) specifically in liver, MUP-tTA mice would be...
This invention claims Modified Vaccinia Ankara (MVA), a replication-deficient strain of vaccinia virus, expressing Human Immunodeficiency Virus (HIV) env, gag, and pol genes, where the genes are isolated from Ugandan Clade D isolates, Kenyan Clade A isolates, and Tanzanian Clade C isolates. In a rhesus macaque SHIV model, DNA priming followed by a recombinant MVA (rMVA) booster controlled a highly pathogenic immunodeficiency challenge. Both the DNA and the rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at zero (0) and eight (8) weeks and a single rMVA booster at twenty-four (24) weeks effectively controlled an intrarectal challenge administered seven (7) months after the booster. Additionally, the inventors have generated data showing that inoculations of rMVA induce good immune responses even without DNA priming. The inventors are continuing preclinical work on the vaccine, and...
Enzymes that degrade mannose to prevent the formation of bacterial-fungal biofilms, which cause dental cavities Problem: Dental cavities are among the most common oral diseases among children and adults in the United States, with treatments for this condition exceeding $81 billion annually. Dental cavities occur when the bacteria Streptococcus mutans feeds off residual sugar on teeth and produces tooth-decaying lactic acid. Additionally, S. mutans can cause even more severe tooth decay when it associates with the fungus Candida albicans. A surface-bound carbohydrate, mannose mediates synergistic growth of bacteria/fungus colonies by helping the two species bind to each other. Disruption of mannose-mediated bacterial-fungal biofilms interaction on teeth would prevent severe dental cavities caused by these two pathogenic microorganisms. Solution: The technology is mannan-degrading enzymes (MDEs) which break down mannose on Candida...
Summary: The National Center for Complimentary and Integrative Health (NCCIH) seeks licensees and/or commercial partners to develop topical formulations of margaric acid to treat allodynia, neuropathy, and pain caused by chronic inflammation. Description of Technology: Some existing therapies for treatment of pain are administered systematically and have significant side effects, such as addiction and drowsiness. Alternative therapy that does not impair normal touch function could be used to treat pain caused by mechanical injury or chronic inflammation. Administration of margaric acid was shown to ameliorate pain in mouse models of pain. In vitro data shows that margaric acid counteracts PIEZO2 (Piezo-type mechanosensitive ion channel component 2) potentiation evoked by bradykinin (i.e. a peptide that promotes inflammation) by reducing the mechanocurrents up to non-inflammatory levels. Margaric acid seems to be specific to target...
Retinal Degenerations (RD) are the leading cause of blindness in the United States. The degeneration of the Retinal Pigment Epithelium (RPE) is associated with various types of RD such as Stargardt’s disease, retinitis pigmentosa, choroideremia, Late-Onset Retinal Degeneration (L-ORD), and Age-related Macular Degeneration (AMD). The RPE as a layer of cells in the back of the eye. Therefore, it is essential to maintain the health and integrity of retinal photoreceptors. RPE dysfunction and degeneration leads to photoreceptor cell death and vision loss, a common factor among several forms of RD. To resolve these challenges, researchers at the National Eye Institute (NEI) generated iPS cells from two L-ORD patients with a dominant mutation in CTRP5 protein and two of their unaffected siblings. They then differentiated all iPS cells into authenticated RPE cells. A comparative analysis of RPE differentiated from these iPS cells showed...
Purines such as adenosine and ATP have been shown to play a wide array of roles in biological systems such as inter alia, modulator of vasodilation and hypotension, muscle relaxant, central depressant, inhibitor of platelet aggregation, regulator of energy supply/demand, responder to oxygen availability, neurotransmitter and neuromodulator. All P1 and P2 receptor nucleoside ligands suffer from chemical instability that is caused by the labile glycosidic linkage in the sugar moiety of the nucleoside. However, it has been found that relatively few ribose modifications are tolerated by the presently known agonists and antagonists of P1 and P2 receptors. The NIH announces a new technology wherein a new class of nucleoside and nucleotide analogs has been identified that serve as selective agonists or antagonists for P1 and P2 receptors. The technology relates to a chemical modification of purines and pyrimidines, which provide enhanced...
The invention provides identification methods for agents which inhibit the Jak-STAT signaling transduction pathway. Drugs identified by these methods are candidates for the treatment of proliferative disorders dependent on the Jak-STAT pathway, including those caused by HTLV-1. In addition, such agents may be potent immunosuppressive drugs with potential applications not only for organ transplantation but also for treatment of autoimmune diseases. Source institute: NHLBI. Inventors: Leonard, Warren.
This technology includes a method for differentiating human induced pluripotent stem cells (hiPSCs) into stable chondrocytes, capable of producing cartilage, and their use in cartilage repair in human injury and degenerative diseases. In suspension culture, hiPSC aggregates demonstrate gene and protein expression patterns similar to articular cartilage. Transplantation of cells from the aggregates into a mouse/rat femoral articular cartilage defect leads to the formation of stable, hyaline-like cartilage that persists for up to 5 months in immunocompromised mice and rats, demonstrating that hiPSC could potentially be used to regenerate cartilage in humans with similar defects. A potential application includes the treatment of osteoarthritis (OA), a disease characterized by the permanent loss of articular cartilage that lines joint surfaces. Commercial applications: In vivo long-term transplantation of hIPSC-derived chondrocytes can...
CDC researchers have developed algorithmic methods for determining sigmoid curve optimums and calculating component concentrations. Sigmoid curves are commonly generated in bioassays and used to calculate results. Various techniques have been used to define the curve, analyze the observations, and calculate a concentration. This technology is an algorithmic approach to identifying the usable portion of a sigmoid curve. This approach is more objective than other methods, reducing the variability introduced by individuals and/or by repetition and allows substantially higher throughput in a situation where a lot of samples are being analyzed using the same assay. Commercial applications: Observation and data analysis. Determining concentrations. Improving calculations and estimations. Enhancing consistency and reproducibility of outcomes for bio and chem assays. Competitive advantages: Less output-data subjectivity than alternate...
OphthalmologyOncologyInfectious DiseaseCardiometabolicInflammationCell/Gene TherapyBiologicDiagnostic / BiomarkerAI / ML
The retinal pigment epithelium (RPE) is a cell monolayer with specialized functions crucial to maintaining the metabolic environment and chemistry of the sub-retinal and choroidal layers in the eye. Damage or disease causing RPE cell loss leads to progressive photoreceptor damage and impaired vision. Loss of RPE is observed in many of the most prevalent cases of vision loss, including age related macular degeneration (AMD) and Best disease. Retinal degenerative diseases linked to loss of RPE result in a substantial economic, social, and healthcare burden for individuals and governments worldwide. Currently, no Food and Drug Administration (FDA) approved treatments exist for AMD. Importantly, AMD vision loss is linked to RPE cell atrophy; thus, transplant and replacement of the lost RPE with healthy and functional RPE cells might be a treatment for AMD and other retina diseases. Healthy functional RPE can be grown/differentiated from...
Cardiovascular disease is a major health risk throughout the industrialized world. Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities. It is also the principal cause of death in the United States. This invention portrays a method for diagnosing decreased vascular function, detecting increased cardiovascular risk and diagnosing atherosclerosis. An embodiment includes assaying the number of endothelial progenitor cells and treating a subject with decreased vascular function by administering a therapeutically effective amount of endothelial progenitor cells. Source institute: NHLBI. Inventors: Quyyumi, Arshed, Hill, Jonathan, Finkel, Toren.
The invention can be used to develop tests that are much more rapid than conventional tests for determining drug resistance. It relates to the discovery that a putative gene of Mycobacterium tuberculosis (MTb) with no previously identified function is responsible for the ability of the bacteria to activate a class of second line thioamide drugs used for MTb infections. The gene, termed "etaA", codes for the synthesis of a monooxygenase, the enzyme responsible for the oxidative activation of the drugs. Mutation in the etaA gene leads to the expression of mutated, inactivated enzyme, thus resulting in thioamide drug-resistant bacteria. The significance of this discovery is that now, resistance to the class of thioamide drugs in clinical isolates can be identified in a relatively short time, eliminating the need to perform lengthy culturing procedures. The invention claims test methods for determining resistance to thioamide drugs by...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for development of papilloma-infiltrating lymphocytes (PIL) as treatment for patients with chronic human papillomavirus (HPV) 6 or 11 infections. Description of Technology: Recurrent Respiratory Papillomatosis (RRP) and anogenital condyloma are caused by chronic infection with human papillomavirus (HPV) types 6 or 11. These conditions lead to the development of papillomatous growths in different regions of the body – RRP affects the upper aerodigestive tract, while condylomas involve the anogenital area. In RRP, growths in the aerodigestive tract can cause dysphonia, dyspnea, and, in severe cases, airway obstruction, which may lead to recurrent pneumonia or respiratory failure. Current treatment for RRP primarily involves repeated surgical debulking or laser ablation to manage symptoms. However, the virus often persists in a latent...
Summary: NCI seeks commercial partners to co-develop and/or license a novel method for isolation and construction of neoantigen-reactive T-cell receptors (TCRs) from peripheral blood lymphocytes (PBL). Description of Technology: Adoptive cell transfer (ACT) uses tumor infiltrating lymphocytes (TILs) that recognize antigens expressed by cancer cells (neoantigens). Neoantigen specific TIL administration in patients has resulted in long-term regression of certain metastatic cancers. However, current procedures for TIL therapy are highly invasive, labor-intensive, and time consuming. The success of these procedures is limited and differs between patients and histologies. Isolation of neoantigen reactive TCRs have historically been challenging due to very low precursor frequencies of these T-cells as well as lack of technical advances that can determine phenotypic markers of these cells from the blood. Researchers at the National Cancer...
CAR-T cells are PEGylated to block the interactions with monocytes and macrophages to reduce the side effects of CAR-T cell therapies (cytokine release syndrome and neurotoxicity). Problem: CAR-T cell therapies lead to many adverse side effects such as cytokine release syndrome (CRS) and neurotoxicity. It has been shown that 20-70% of patients receiving CD19 CAR-T cell therapy will develop CRS. This gives rise to many symptoms such as high fever, increased levels of acute-phase proteins, and respiratory and cardiovascular insufficiency, and if left untreated, could lead to multiple organ dysfunction or patient death. Solution: A method involving PEGylation of CAR T cells to alleviate side effects of CAR T cell immunotherapies. Polyethylene glycol (PEG) acts as a biodegradable polymeric spacer to block cell-to-cell interactions. PEG600k, MW 600k has PEG length of about 6 μm, which is much longer than the other PEGs tested and may...
Bone-loss-related diseases, such as periodontitis, are characterized by an imbalance between the formation and activity of osteoblasts and osteoclasts, leading to bone loss. There are several signaling pathways that participate in the osteoclastogenesis process. Finding inhibitors of these pathways and other osteoclastogenesis-related pathways may have an effect on bone-loss diseases. Researchers at the National Cancer Institute (NCI), in collaboration with researchers at the University of Campinas, Brazil, have identified cinnamolyoxy-mammeisin (CNM), a 4-phenylcoumarin, which can be isolated from Brazilian geopropolis, as active against osteoclastogeneis pathways. CNM demonstrates anti-inflammatory activity and inhibition of oral bone loss in a mouse model of periodontitis. Competitive Advantages: Lack of cytotoxicity. Commercial Applications: Alternative to commercial antiresorptive agents. Source institute: NCI. Inventors:...
Description of Technology: Axonal injury and subsequent neuronal death underpin the pathology of many neurological disorders from acute neural injuries (motor vehicle crashes, combat related injuries, traumatic brain injuries) to neurological diseases (multiple sclerosis, glaucoma). In the central nervous system (CNS), microglia help respond to CNS injuries by mediating the immune response and increasing inflammation at the site of injury. Scientists at the National Eye Institute (NEI) have discovered a novel method of reducing neuronal death by using Dimethyl Malonate (DMM), a compound that inhibits the activity of succinate dehydrogenase (SDH). Using DMM on an optic nerve crush model in ground squirrels, DMM helped reduce the pro-inflammatory response of microglia via decreasing succinate levels or reducing the SDH activity. In the same model, treatment also improved the retinal function compared to controls. Additionally,...
X-linked retinoschisis (XLRS) is an inherited, monogenetic ocular disease caused by mutations in the retinoschisin (RS1) gene, resulting in the development of cystic cavities throughout the retina and leading to juvenile macular degeneration. Approximately 1:15,000 males in the US are affected, classifying the condition as an orphan indication. The National Eye Institute (NEI) has developed a tissue-specific gene therapy approach based upon adeno-associated virus (AAV) mediated delivery of the full coding sequence for human retinoschisin to retinal cells under the control of a retinoschisin promoter. Delivery and expression of AAV-RS1 is a novel invention for the restoration of RS1 expression in those suffering from XLRS, presenting a potential cure to an untreatable disease. Restoration of both structure and function was demonstrated in a preclinical mouse model. A single site Phase I/IIa clinical trial of AAV-RS1 using GMP-grade...
This invention relates to materials and methods associated with polymorphic variants in two enzymes involved in folate-dependent and one-carbon metabolic pathways important in pregnancy-related complications and neural tube birth defects: MTHFD1 (5,10-methylenetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, 10-formyltetrahydrofolate synthase) and methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L). These enzymes are extremely important in the promotion of DNA synthesis, a process that is critical for normal placental and fetal development. Recently, the inventors have discovered that a MTHFD1 polymorphism is also a maternal genetic risk factor for placental abruption, premature separation of a normally implanted placenta. This polymorphism may also be a risk factor for first and second trimester miscarriages. Diagnostic and therapeutic methods are provided in this invention involving...
This CDC invention provides methods for preventing or treating inflammatory response-linked, infection induced pathologies, which are mediated by endogenous substance P. Substance P is a naturally-occurring and major pro-inflammatory neuromediator or neuromodulator, and elevated levels of substance P have been implicated in numerous inflammation-associated diseases. More specifically, this technology entails administration of anti-substance P antibodies or anti-substance P antibody fragments to a subject in need, thereby inhibiting the activity of endogenous substance P. Small molecule anti-inflammatory agents currently employed to treat inflammation frequently cause adverse side effects, such as gastrointestinal discomfort and decreased blood clotting efficiency. Use of steroid-based anti-inflammatory drugs may result in reduced adrenal gland function and generalized immune system inhibition. This technology specifically targets and...
A method that maintains the viability and function of NK cells following cryopreservation, enabling the production, storage, and transportation of therapeutic doses of NK cells to treatment centers. Problem: There is a growing interest in using NK cells as immunotherapies for diseases such as cancer. Making commercially viable NK cell therapies requires large-scale production of NK cells which need to be cryopreserved for storage and transportation to the clinic. However, NK cells do not cryopreserve well; there is a significant loss of cells after cryopreservation, and those that survive are less functional. Poor recovery of NK cells after cryopreservation is a significant barrier to successful commercial development of NK cell therapies. Solution: Pre-treatment of NK cells with the cytokines, interleukin (IL)-15 & 18, under the correct conditions before cryopreservation enables a cryopreserved product of equipotency post thaw...
The invention provides a method of diagnosing X-linked severe combined immunodeficiency (XSCID) in males or determining whether females are carriers. This method is based upon the presence of either a mutated or truncated IL-2Rgamma gene. The invention also discloses a method of treating XSCID as well as a method for monitoring the therapy. Lastly, the invention provides a promoter which regulates the expression of IL-2Rgamma, a vector comprising a DNA molecule operably linked to the promoter, a cell host that has been transformed with the vector, and a transgenic mouse comprising the promoter or a mutant IL-2Rgamma. Commercial applications: Diagnosing XSCID. Identifying a carrier. Treating XSCID. Monitoring effectiveness of therapy for XSCID. Research reagent. Competitive advantages: Diagnostic test is only way of definitively diagnosing XSCID. Process for diagnosis is completely developed. Source institute: NHLBI. Inventors:...
The identification of more sensitive and specific markers of atherosclerosis that are non-invasive and cost-effective may have profound impacts on public health. One such strategy involves the detection of marker genes or their products in blood or serum. Such markers may help identify high-risk patients with subclinical atherosclerosis who may benefit from intensive primary prevention or they may help determine the activity of established disease for monitoring response to treatment, resulting in more targeted secondary prevention. The present invention relates to methods for detecting atherosclerosis using highly reactive biomarkers (FOS and/or DUSP1) expressed in blood cells or released into serum. Because these markers are also involved in pathogenesis, they may serve as potential targets for drug discovery and for intervention to modify disease progression. Source institute: NHLBI. Inventors: Hwang, Paul.
The invention concerns immunotoxins and methods of making the immunotoxins. Targeting of the immunotoxins occurs via an antibody that is specific to T cells. This allows the specific ablation of malignant T cells and resting T cells. The transient ablation of resting T cells can "reset" the immune system by accentuating tolerizing responses. As a result, the immunotoxin can be used to treat autoimmune disease, malignant T cell-related cancers, and graft-versus-host disease. The toxin portion of the immunotoxin is engineered to maintain bioactivity when produced in yeast, specifically Pichia pastoris . This system allows the production of dimeric antibody fragments with increased binding affinity and potency. Commercial applications: Immunotoxins produced by this method can be used for the treatment of autoimmune diseases such as multiple sclerosis, lupus, type I diabetes, aplastic anemia.. Immunotoxins produced by this method can be...
This CDC developed technology entails a novel method of near real-time elemental analysis of aerosols by corona assisted microwave induced plasma spectroscopy (CAMPS). Analysis of elemental composition of aerosol particles holds significant implications for environmental and workplace pollution monitoring. Various plasma based analytical techniques, including laser-induced breakdown spectroscopy (LIBS) and spark-induced breakdown spectroscopy (SIBS), have been successfully used for multi-elemental analyses in solids, liquids, and gases, including aerosols. However, the characterization of fine and ultrafine aerosols using these techniques is particularly challenging due to small plasma volume, miniscule sample mass, and inferior sampling statistics, often leading to poor detection limits and precision. This technology utilizes a microwave plasma-based detection system for aerosol analysis that features increased microplasma lifetime,...
T cells currently employed for T cell-based immunotherapies are often senescent, terminally differentiated cells with poor proliferative and survival capacity. Recently, however, scientists at the National Cancer Institute (NCI) identified and characterized a new human memory T cell population with stem cell-like properties. Since these T cells have limited quantities in vivo, the scientists have developed methods by which high numbers of these cells can be generated ex vivo for use in T cell-based immunotherapies. Specifically, this invention describes a method for generating the stem cell-like memory T cells by stimulating naive T cells in the presence of GSK-3beta inhibitors. The invention also provides methodology for obtaining the stem cell-like memory T cells by sorting T cell lymphocytes using flow cytometry. These stem cell-like memory T cells display enhanced proliferation and survival upon transfer, have the multipotent...
This invention includes methods for treating or ameliorating fibrosis by inhibiting the interaction between IL-21 Receptor (IL-21R) and IL-21 using either anti-IL-21R monoclonal antibodies (or binding fragments of anti-IL-21R mAbs), anti-IL-21 monoclonal antibodies (or binding fragments of anti-IL-21 mAbs) or soluble IL-21R (or binding fragments of IL-21R). It is believed that the TH2 immune response, induced by IL-21, plays a major role in the in the pathogenesis of tissue fibrosis. Antagonism of IL-21R by anti-IL-21R monoclonal antibodies or the sequestration of IL-21 by soluble IL-21R or anti-IL-21 monoclonal antibodies has been demonstrated to reduce TH2 immune responses associated with fibrosis in animal models. The causes of chronic tissue fibrosis are diverse and the market for a therapeutic that targets fibrosis is large. Fibrosis is associated with diverse causes which include: genetic diseases (such as cystic fibrosis);...
Method for protecting against nephropathy/nephritis through topical administration of a vitamin D3 analog, producing systemic therapeutic effects potentially beneficial in protein-losing nephropathy, lupus nephritis, diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), and genetic nephropathies. Problem: Protein-losing nephropathy, lupus nephritis (a manifestation of Systemic lupus erythematosus), diabetic nephropathy, FSGS, and genetic nephropathies are disorders that damage the glomerular filtration barrier, resulting in proteinuria and progressive renal scarring. Despite differing etiologies, these disorders converge on a common pathway of chronic glomerular injury that progresses to chronic kidney disease and, ultimately, renal failure. More targeted, disease-modifying therapies that avoid broad systemic immunosuppression remain a significant unmet medical need. Solution: This technology leverages topical delivery of...
CDC researchers have developed a method of simultaneously detecting and distinguishing multiple antigens within a biological sample. Epidemiological and vaccine studies require species serotype identification. Current methods of serotyping are labor intensive and can easily give subjective, errant results. This technology utilizes serotype specific antibodies bound to fluorescent beads, allowing for simultaneous single tube capture and detection of multiple antigens in one rapid, high-throughput flow cytometry assay. Such technology has an extremely wide range of useful applications, including but not limited to complex serotyping investigations for vaccine development and formulation, as a tool for rapid clinical prognosis or diagnosis, and the assay can be formatted as a kit for any number of laboratory research uses. Commercial applications: Complex serotyping and/or multi-antigen composition investigations. Tool for clinical...
The invention concerns immunotoxins and methods of using the immunotoxins for the treatment of rejection response in a patient, including graft-versus-host disease and transplantation of organs, tissues and cells into a host. In a specific embodiment of the invention, the transplant involves pancreatic islet cells. The immunotoxins are targeted via an antibody that is specific to T cells. This allows the specific ablation of resting T cells, resulting in an accentuation of immune tolerizing responses and an increased tolerance to transplants and grafts. The toxin portion of the immunotoxin is genetically engineered to maintain bioactivity when recombinantly produced in Pichia pastoris . Data are available in transgenic animals expressing human CD3epsilon which supports the effects of the immunotoxin against T cells. Commercial applications: Use of immunotoxins decreases T cell population, allowing greater host immune tolerance of...
Hematopoietic and pluripotent stem cells can be differentiated into T cells with potential clinical utility. Current approaches for in vitro T cell production rely on Notch signaling and artificial mimicry of thymic selection. However, these approaches result in unconventional or phenotypically aberrant T cells; which may lead to unpredictable behavior in clinical use. Thus, there exists a need for improved methods of generating conventional T cells in vitro from stem cells. Researchers at the National Cancer Institute (NCI) have developed a novel method for the in vitro differentiation of induced pluripotent stem cells (iPSCs) into induced pluripotent stem cell thymic emigrant (iTE) cells. Cells produced by this method are functionally equivalent to natural naïve CD8αβ+ T cells. The approach utilizes improved fetal thymic organ culture methodology to mature progenitor cells into conventional T cells in the presence of extrinsic Notch...
Dopamine is a major neurotransmitter in the central nervous system and among other functions is directly related to the rewarding effects of drugs of abuse. Dopamine signaling is mediated by D1, D2, D3, D4 and D5 receptors. The dopamine D3 receptor is a known target to treat a variety of neuropsychiatric disorders, including substance use disorders (e.g. cocaine and opioid), schizophrenia and depression. Despite extensive efforts, it has proven difficult to identify a lead molecule that selectively binds to D3 receptors (versus D2 receptors, for example), with the desired pharmacological and pharmacokinetic profile. For example, metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. The library of compounds of this technology is designed to have high affinity and specificity for the dopamine D3 receptor. Preliminary studies at...
The National Cancer Institute's Laboratory of Pathology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutics targeting vasodialation. Nitric oxide (NO) plays an important role as a major intrinsic vasodilator, and increases blood flow to tissues and organs. Disruption of this process leads to peripheral vascular disease, ischemic heart disease, stroke, vascular insufficiency associated with diabetes, and many more diseases that are significant. Researchers at the NIH have discovered that the matrix protein thrombospondin-1 blocks the beneficial effects of NO, and prevents it from dilating blood vessels and increasing blood flow to organs and tissues. Additionally, the inventors discovered that this regulation requires interaction with thrombospondin-1's cell receptor CD47. Murine studies revealed that, in the presence of NO,...
The technology offered for licensing is in the field of vaccinia-based recombinant vaccines. In particular the invention relates to methods of stabilizing the recombinant virus, thus resulting in efficient production of the vaccine and efficient expression of the inserted gene. Stabilization of the recombinant virus is achieved by the insertion of the exogenous gene into an intergenic region (IGR) of the viral genome (i.e. Modified Vaccinia Ankara, MVA), where the IGR is flanked by open reading frames of conserved poxvirus genes. Furthermore, the invention relates to plasmids vectors useful to insert the exogenous DNA into the genome of a vaccinia virus. Stability can be further enhanced by incorporating silent mutations that decrease the lengths of homopolynucleotide runs in the foreign gene. Commercial applications: Efficient production of vaccinia-vectored vaccines for infectious diseases and other diseases such as cancer....
This technology includes a new method to prepare very long chain fatty acids (VLCFA), which does not use the previously reported toxic mercury amalgam, for use as nutritional supplements, and as therapeutics for various diseases. The key coupling step involves an organocopper mediated coupling of the Grignard regent derived from the bromo alkyl tetraene with a bromoalkyl containing a protected alcohol. After the coupling the alcohol Is deprotected and oxidized to prepare the very long fatty acid. The synthetic approach is flexible and can be used to prepare the other VLCFA compounds. Similar methods are used in the chemical industry for preparation of fine chemicals and should allow the synthesis of large quantities of material. Commercial applications: Our product with significantly high purity could be used as nutritional formulas and supplements, and as therapeutics for various diseases, disorders, and conditions. Competitive...
Formation of biofilms (microorganisms) on medical devices is a common cause of infection and device replacement. For example, biofilm formation on urinary catheters is associated with the development of catheter-associated urinary tract infections (CAUTI), and recent studies indicate that approximately 9% of HAIs stem from CAUTI. Urinary catheters are also thought to be one of the largest reservoirs of nosocomial antibiotic-resistant pathogens. The related increases in patient morbidity, mortality, and costs with CAUTI are substantial. CDC and partner researchers have designed methods for controlled attachment of bioactive bacteriophages to medical devices for reducing bacterial colonization and regulating biofilm development. With collaborators at the Georgia Institute of Technology, CDC has developed and patented a novel approach to covalently attach bacteriophages to hydrogel-coated catheters. These tethered bacteriophages can...
Scientists at NCATS have developed an analog of Methotrexate (MTX) that incorporates the proteasome-targeting properties of E3-ubiquitin ligase small molecule ligands (MTX-PROTACs) to directly bind to the MTX target dihydrofolate reductase (DHFR) and mark the protein for proteasomal degradation. This unique property may dramatically lower the therapeutic dose required in a treatment setting. The initial series of molecules that utilized differing E3 ligase ligands and linkers to MTX demonstrated dramatically differential effects on the cellular turnover of DHFR in a lymphoma B-cell (HBL-1) line. These results suggested that it was possible to achieve targeted tissue selectivity with specific analog designs. Further, in comparative cell culture studies with the parent MTX, scientists observed that MTX appeared to lead to an increase in cellular DHFR, a mechanism that may allow some cancer cells to continue to proliferate once MTX...
The present research tool is a knockout mouse model (FPR -/- ) that lacks the high affinity N-formylpeptide receptor (FPR), created by targeted gene disruption. N-formylpeptides derive from bacterial and mitochondrial proteins, and bind to specific receptors on mammalian phagocytes. Since binding induces chemotaxis and activation of phagocytes in vitro, it has been postulated that N-formylpeptide receptor signaling in vivo may be important in antibacterial host defense, although direct proof has been lacking. The inventors have found that FPR -/- mice have no obvious developmental defects and do not develop spontaneous infection when derived in specific pathogen-free conditions. This suggests that, under these conditions, FPR is dispensable. However, when challenged with L. monocytogenes, FPR-deficient mice have accelerated mortality and increased bacterial burden in liver and spleen early after infection, which suggests a role for...
Heterotrimeric G proteins couple signals between GPCRs (G protein coupled receptors) and effectors such as adenylyl cyclase, phospholipase C and ion channels. Among the G proteins are Go and Gi2. Go is highly expressed in the brain and some endocrine tissues while Gi2 is widely expressed throughout the body. The ß?-subunits of Go interact with ion channels, and the a subunit has been shown to inhibit adenylyl cyclase. However a physiological role of the Gi2a has not been determined in a tissue specific manner. In this invention, mice with a floxed allele of the Go-a subunit and mice with a floxed allele of the Gi2a subunit were generated. These transgenic mice can be used to study the function of Go-a and the function of Gi2a in a tissue specific manner. Commercial applications: The Go-a flox mice can be used to identify unknown biomedical functions of Go-a. Thus the mice could be used in developing therapeutics, diagnosis of disease,...
A scalable, parallelized, multi-channel microfluidic device for generating lipid nanoparticles. Problem: Lipid nanoparticles are a promising delivery technology for RNA therapeutics and vaccines. However, there is a lack of formulation strategies that can produce nanoparticles with precisely defined properties that have scalable throughputs ranging from early development to clinical translation. Prior microfluidic technologies have been used to produce lipid nanoparticles with high potency and desirable physical properties, but are limited by their ability to scale to throughputs relevant for clinical studies. Solution: A scalable, parallelized microfluidic device (PMD) that incorporates an architecture that allows for large-scale production of lipid nanoparticles and achieves >100x production rates compared to microfluidic small scale (single channel) lipid nanoparticle formulation strategies. Inventors: David Issadore, Michael...
Hazardous airborne particles pose a risk for health and safety in a variety of environments and thus detection of these small particles is essential. Current particle magnification systems are bulky and require a lot of power for operation, making them unsuitable to easily detect and analyze small particles in mobile and personal settings. CDC/NIOSH scientists have developed a space-saving miniature instrumentation and methods for the direct sampling and analysis of small particles (diameter < 300-400nm). The systems can effectively sample air at a rate of a few liters per minute and concentrate the particulate matter into microliter or milliliter liquid samples. The novel system uses proton exchange membranes to grow small particles for optical detection using standard methods. Further, these methods allow the system to separate condensation and aerosol flow to enhance user mobility. Moreover, the described methods use inexpensive...
Podocytes, cells of the visceral epithelium in the kidneys, are a key component of the glomerular filtration barrier. As such, they play a vital role in glomerular disorders, which are a major cause of chronic kidney disease. Examples of these disorders include focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, and diabetic nephropathy. The inventors have developed a conditionally-immortalized mouse podocyte cell line with tightly controlled conditional gene expression. The cell line has been conditionally immortalized through the introduction of the H-2Kb-tsA58 transgene, which is a temperature-sensitive mutant of the SV40T antigen. Inducible gene expression is tightly controlled through two introduced transgenes, podocin-rtTA and CMV-tTS, that produce a "Tet-on" system wherein gene expression is induced by tetracycline or doxycycline. The combination of the two transgenes for Tet-on gene...
The ubiquitous use of antibiotics has resulted in the selection of bacteria that are relatively resistant to these drugs. Furthermore, few drugs are effective against viral and fungal microorganisms. There is therefore a continuing need to identify novel agents that reduce or inhibit the growth of such microorganisms, or to identify ways of modifying existing agents in order to give them superior antimicrobial activities, or to identify agents that may recruit inflammatory cells. Defensins are broad-spectrum antimicrobial molecules that act against infectious agents and play important roles in the innate immune defense in vertebrates. These molecules exhibit a wide range of antimicrobial activities, including cytotoxicity towards bacteria cells, but are also cytotoxic for mammalian cells, which limits their usefulness as antimicrobial agents. The NIH announces the creation of modified defensins through their arginine residues. These...
A library of bi-phosphonate ionizable lipids and LNP formulations to facilitate mRNA delivery to the bone microenvironment. Problem: The increasing prevalence of skeletal diseases such as osteoporosis, osteoarthritis and bone cancer have motivated efforts to target the bone microenvironment therapeutically. However, therapeutic agents must overcome multiple challenges in order to reach the key compartments of bone including reduced blood flow compared to highly vascularized tissue, poor penetration of the blood-bone marrow barrier, insufficient perfusion of bone, and low chemical affinity for bone mineral. Solution: Biphoshphonate (BP) lipid-like materials improve the ability of LNPs to deliver encapsulated mRNAs to the bone microenviroment. Enhanced protein expression is observed in leg bone after in-vivo injection, and within cells of both the myeloid and lymphoid lineages arising from the bone marrow compartment. Inventors: Michael...
Griffithsin (GRFT) is a lectin with potent antiviral properties that is capable of preventing and treating infections caused by a number of enveloped viruses (including HIV, SARS, HCV, HSV, and Japanese encephalitis) and is currently in clinical development as an anti-HIV microbicide. In addition to its broad antiviral activity, GRFT is stable at high temperature and at a broad pH range, displays low toxicity and immunogenicity, and is amenable to large-scale manufacturing. Native GRFT is a domain-swapped homodimer that binds to viral envelope glycoproteins and has displayed mid-picomolar activity in cell-based anti-HIV assays. Researchers at NCI's Molecular Targets Lab developed synthetic proteins that comprise two (or more) obligate monomers (“mGRFT”) joined by an amino acid linker to form tandemers (“mGRFT tandemers”). Each obligate monomer is generated by the addition of Gly-Ser residues in the hinge region of wild-type GRFT. Two...
Many chemotherapeutic agents cause significant cytotoxicity to non-cancer ("normal") cells, resulting in undesirable side-effects and often limiting the dose and/or duration of chemotherapy that can be administered to a patient. Investigators at the National Cancer Institute’s Laboratory of Pathology have demonstrated that deficiency or blockade of the ubiquitously expressed receptor CD47 results in remarkable cell and tissue protection against ischemic and radiation stress. Antagonists of CD47 or its ligand THBS1/thrombospondin 1 enhance cell survival and preserve their proliferative capacity. The researchers found that using CD47-modulating compounds in combination with a chemotherapeutic agent increases the efficacy of that agent against inhibiting tumor growth. This discovery builds on previous discoveries of antibodies, antisense morpholino oligonucleotides, and peptide compounds that modulate CD47. The results have been observed...
This invention provides materials, methods, and assays for detecting HIV-1 groups M and O and optionally HIV-1 group N and simian immunodeficiency virus-cpz (SIV-cpz). Specific nucleic acid primers for hybridization, amplification, and detection of HIV-1 are also provided for. The nucleic acid amplification assays can detect small concentrations of HIV-1 and are also useful for quantitative examinations of viral load concentrations within biological samples. Commercial applications: Blood and plasma donation screening. Diagnostic detection of HIV-1. Public health programs. Monitoring HIV treatment and disease inhibition/progression. Competitive advantages: Broad-use, generic viral detection for groups M, N and O HIV-1, and also SIVcpz. Requires minute quantities of virus for use, making this assay ideal for confirmation of early-stage infection. Sensitive and highly specific. Easily formulated for kits. Established efficacy in patient...
The four dengue virus (DENV) serotypes (DENV-1 to DENV-4) are the most important arthropod-borne flaviviruses in terms of morbidity and geographic distribution. Up to 100 million DENV infections occur every year, mostly in tropical and subtropical areas where vector mosquitoes are abundant. Infection with any of the DENV serotypes may be asymptomatic or may lead to classic dengue fever or more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which are increasingly common in the dengue endemic areas. Immunity to the same virus serotype (homotypic immunity) is life-long, whereas immunity to different serotypes (heterotypic immunity) lasts 2–3 months so that infection with a different serotype virus is possible. DHF/DSS often occurs in patients with second, heterotypic DENV infections or in infants with maternally transferred dengue immunity. Severe dengue is a major cause of hospitalization, and fatality rates vary...
Concerns that variola (smallpox) virus might be used as a biological weapon have led to the recommendation of widespread vaccination with vaccinia virus. While vaccination is generally safe and effective for prevention of smallpox, it is well documented that various adverse reactions in individuals have been caused by vaccination with existing licensed vaccines. Vaccinia immune globulin (VIG) prepared from vaccinated humans has historically been used to treat adverse reactions arising from vaccinia immunization. However, VIG lots may have different potencies and carry the potential to transmit other viral agents. Chimpanzee Fabs against the B5 and A33 outer extracellular membrane proteins of vaccinia virus were isolated and converted into complete mAbs with human gamma1 heavy chain constant regions. The two mAbs displayed high binding affinities to B5 and A33. The mAbs inhibited the spread of vaccinia virus as well as variola virus...
Early work by Hammond at al. showed gamma globulin to be effective for the prevention of poliomyelitis. Therefore, passive immunotherapy could be another way to treat chronic excretors. Even though prior attempts to use intravenous immunoglobulin (IVIG) and breast milk were unsuccessful, there is reason to think that higher doses of antipoliovirus antibodies could result in complete clearance of poliovirus from chronically infected individuals. Six poliovirus-neutralizing MAbs were recovered from a combinatorial Fab phage display library constructed from bone marrow-derived lymphocytes of immunized chimpanzees. The six MAbs neutralized vaccine strains and virulent strains of poliovirus. Five MAbs were serotype specific, while one MAb cross-neutralized serotypes 1 and 2. Both serotype 2-specific antibodies recognized antigenic site 1. No escape mutants to serotype 3-specific MAbs could be generated. The administration of a serotype...
Hepatitis B virus (HBV) chronically infects over 300 million people worldwide. Many of them will die of chronic hepatitis or hepatocellular carcinoma. The present technology relates to the isolation and characterization of a novel neutralizing chimpanzee monoclonal antibody to HBV. The antibody was identified through a combinatorial antibody library constructed from bone marrow cells of a chimpanzee experimentally infected with HBV. The selected monoclonal antibody has been shown to react equally well with wild-type HBV and the most common neutralization escape mutant variants. Therefore, this monoclonal antibody with high affinity and broad reactivity may have distinct advantages over other approaches to immunoprophylaxis and immunotherapy of chronic HBV infection, as most of the monoclonal antibodies currently in use are not sufficiently and broadly reactive to prevent the emergence of neutralization escape mutants of HBV. This...
Bacillus anthracis is the causative agent of anthrax and is surrounded by a polypeptide capsule of poly-gamma-D-glutamic acid (gammaDPGA). gammaDPGA is poorly immunogenic and has antiphagocytic properties. The bacterial capsule is essential for virulence. Antibodies to the capsule have been shown to enhance phagocytosis and killing of encapsulated bacilli. These antibodies in combination with antibodies that neutralize the toxins of B. anthracis could provide enhanced protection by their dual antibacterial and antitoxic activities. Such antibodies would be especially useful for antibiotic-resistant strains. In order to obtain therapeutically useful anti-gamma DPGA monoclonal antibodies (MAbs), the inventors immunized chimpanzees with conjugates of 15-mer glutamic acid polymers to immunogenic protein carriers (recombinant protective antigen (PA) of B. anthracis ). After several immunizations, chimpanzees developed strong immune...
Human mesothelin is overexpressed by various cancers such as synovial sarcoma, mesothelioma, and ovarian, lung, esophageal, and gastric cancers. This selective expression on certain cancers suggests that mesothelin is an excellent target for anticancer therapeutics. However, a large fragment (“the shed portion”) of mesothelin is constantly shed from cells, and all current anti-mesothelin antibodies bind to the shed portion. As a result, the therapeutic efficacy of these antibodies has been low because they are unable to exert their therapeutic effect on the cell before their binding region is shed. Fortunately, a piece (“the stalk”) of mesothelin remains attached to the cell surface after shedding. Since antibodies to the stalk would remain bound to diseased cells, they can be more effective in killing cancer cells than currently available anti-mesothelin antibodies. Scientists at the National Cancer Institute (NCI) have invented...
Dengue Virus (DENV) non-structural protein 1 (NS1) is secreted in blood during the acute phase of viremic DENV infection. While there are commercially available ELISA assays for DENV NS1 detection, these tests have limited sensitivity (50-70%), do not determine the serotype of the infecting DENV, do not detect all four serotypes equally, or are less sensitive in subsequent DENV infections. There is a critical need for serotype specific diagnostics to inform public health and potentially clinical care interventions. CDC developed three hybridoma cell lines and three DENV-4 serotype-specific monoclonal antibodies (mAbs) for the detection of DENV-4 NS1 in human serum. These mAbs do not cross-react with other dengue virus subtypes (DENV 1, 2, and 3) or other flaviviruses (e.g., West Nile virus or Yellow fever virus) and can be used to develop ELISA and rapid diagnostic tests for dengue detection in resource poor settings. A NS1 DENV...
Anthrax, whether resulting from natural or bioterrorist-associated exposure, is a constant threat to human health. The lethality of anthrax is primarily the result of the effects of anthrax toxin, which has 3 components: a receptor-binding protein known as "protective antigen" (PA) and 2 catalytic proteins known as "lethal factor" (LF) and "edema factor" (EF). Although production of an efficient anthrax vaccine is an ultimate goal, the benefits of vaccination can be expected only if a large proportion of the population at risk is immunized. The low incidence of anthrax suggests that large-scale vaccination may not be the most efficient means of controlling this disease. In contrast, passive administration of neutralizing human or chimpanzee monoclonal antibody to a subject at risk for anthrax or exposed to anthrax could provide immediate efficacy for emergency prophylaxis against or treatment of anthrax. Four monoclonal antibodies...
Fentanyl is a synthetic opioid drug approved by the Food and Drug Administration for use as an analgesic (pain relief) and anesthetic. However, synthetic opioids, such as fentanyl, are prone to abuse and are the primary drivers of overdose related deaths in the United States. As little as two milligrams of fentanyl can be lethal. Furthermore, structural variants of fentanyl, often mixed with other drugs or counterfeit pills are illegally distributed without the user’s knowledge. There is great need for assay methods that could simultaneously detect fentanyl variants and provide information about their cross-reactivity and the metabolites. Law enforcement and emergency responders who encounter overdose victims or illegal drugs in the field would benefit from reliable, rapid, inexpensive, and easily interpreted assays to better treat patients, protect themselves from exposure, and trace the origins of the hazardous compounds. Using...
Available for licensing are monoclonal antibodies against HIV-1 viral protein R (Vpr) and the respective hybridoma cell lines expressing the same. The antibodies provide a means for detecting HIV-1 Vpr. Currently, the mechanism of HIV pathogenesis believed to involve viral replication inside immune cells and other cells. At present, there are no clinical assays for detecting HIV-1 Vpr. Vpr circulates at detectable levels in the blood and is likely derived from degraded virions or released from infected cells. Vpr facilitates viral replication and disrupt normal cell function. Thus measurement of Vpr levels in blood, extracellular fluid, and tissue may be of benefit in understanding the pathogenesis of HIV-1 infection and its myriad complications. The hybridoma cell lines (9F12 and 10F2) were selected from a group of hybridoma cell lines. These antibodies can be used for detection, including immunoasssays (ELISA) and...
A child's growth is dependent on the proper functioning of the growth plate, a specialized cartilage structure located at the ends of long bones and within the vertebrae. The primary function of the growth plate is to generate new cartilage, which is then converted into bone tissue and results in the lengthening of bones. Failure of the growth plate to function properly can result in short stature or sometimes a skeletal dysplasia, such as achondroplasia, in which the bones are not just short but also malformed. Current treatments for severe short stature and skeletal growth disorders are limited. Recombinant human growth hormone (GH) is typically used, but the results are often less than optimal and growth hormone has potential adverse effects. Researchers at the Eunice Kennedy Shriver National Institute on Child Health and Human Development (NICHD) Section on Growth and Development , collaborating with the NCI Laboratory of...
Summary: NICHD is seeking research co-development partners and/or licensees for development of this invention as a male contraceptive. Description of Technology: The options for male contraceptives are limited. Research is ongoing to develop a male contraceptive based on hormonal activity. Testosterone is one of the hormones necessary in producing sperm. Testosterone is absolutely required as a hormone for male fertility. Derivatives of testosterone for male contraceptives currently in clinical trials are associated with estrogenic deficiency. This deficiency can cause several issues including, but not limited to, bone density loss, risk of obesity, cardiovascular disease, and/or ineffective carbohydrate or lipid metabolism. Researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) have developed a new chemical entity and related embodiments of the following formula: Formula 1. This...
This technology describes monoclonal antibodies against mouse chemokine (C-X-C motif) ligand 9 (CXCL9), also known as Monokine induced by gamma interferon (Mig). CXCL9 is a secreted protein that functions to attract white cells and increased expression of CXCL9 has been linked to several diseases. The inventors at the NIH generated over 100 anti-mouse CXCL9 antibodies from a CLXL9/Mig knockout mouse and further characterized several antibodies to show neutralization of CXCL9. As such, these antibodies could be used to measure concentrations of mouse CLXL9 in laboratory samples and block the activity of CXCL9 in injected mice. These antibodies are suitable for ELISA and Western blot. The antibodies have not been tested in flow cytometry or immunohistochemistry, but may also be useful for these applications. Commercial applications: ELISA assays for detection and measurement of CXCL9.. Neutralization of CXCL9 activity in mouse models...
Cerebral Cavernous Malformation (CCM) is a brain disease affecting up to 0.5% of the worldwide population. CCM is characterized by grossly dilated vessels prone to leaking and hemorrhage which result in severe headaches, seizures, and strokes. Inherited forms of the disease are due to mutations in one of three loci, CCM1, CCM2, and CCM3. Prior efforts to develop mice with targeted null mutations in Ccm1 , Ccm2 , or Ccm3 have been unsuccessful, as such mutations result in embryonic death. The inventors have developed the first mouse model available for the study of CCM, in which mouse Ccm2 can be conditionally deleted in blood-accessible and endothelial cells, resulting in neurological defects, ataxia, and brain hemorrhages consistent with the human disease. The model was generated through a cross of C57BL/6 Ccm2 -floxed mice with C57BL/6 MX-1-Cre mice, which permits inducible ablation by polyinosinic:polycytidylic acid (pIpC). Source...
Diabetic nephropathy (DN) is the leading cause of renal failure and is characterized by proteinuria that progresses to renal inflammation and decline in the glornerular filtration barrier (GFB). Podocytes are specialized epithelia cells in the glomerular capsule that have a role in filtration of blood and maintaining the integrity of the GFB; dysfunction of these cells plays a significant role in the pathogenesis of DN. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in inflammatory diseases. In the present invention, mice with a podocyte-specific deletion of sEH (pod-sEHKO) were generated to determine the effects of podocyte sEH on renal function. These mice showed moderate improvement in kidney function and systemic glucose homeostasis in normoglycemia and a significant improvement in hyperglycemia. Histology of the kidneys of these animals and in vitro assays with mouse podocytes...
NF-kB has been found to be important in immune responses, cell proliferation, apoptosis, and in organ development. Several years ago it was discovered that an IKKgamma/NEMO protein was essential as an adaptor molecule to mediate TNF-alpha, IL-1, and oncoprotein induced activation of NF-kB. Mutation in IKKgamma/NEMO also results in two human genetic diseases, Familial incontinentia pigmenti and hypohidrotic/anhidrotic ectodermal dysplasia. The NIH announces mouse monoclonal antibodies to IKKgamma/NEMO that are far superior to other immunological reagents. It is anticipated that the antibodies would have both research and diagnostic capabilities. Source institute: NIAID. Inventors: Jeang (Estate), Kuan-teh.
Disease caused by Streptococcus pneumoniae (pneumococcus) is an important cause of morbidity and mortality in the United States and developing countries. Pneumococcal disease is prevalent among the very young, the elderly and immunocompromised individuals. This invention is an improved, immunogenic peptide construct consisting of a combination of antigenic epitopes of the PsaA (37-kDa) protein from S. pneumoniae . In addition, the peptides of the invention have the capability of serving as specific immunogens in a subject, effectively eliciting the production of antibodies and conferring protective immunity against S. pneumoniae infection following immunognen administration. Commercial applications: Development or improvement of S. pneumoniae vaccines. Public health vaccination programs. Clinical serodiagnostic development. Competitive advantages: May provide better immune protection than current, single-epitope based vaccines....
Hyperthermia has been used extensively and successfully in the treatment of solid tumors. For accessible solid tumors with impressive efficacy not amenable to surgery, ablative hyperthermia (>55°C for 20 s to 15 min) has been used as a definitive treatment. By contrast, for both radiotherapy and chemotherapy, mild hyperthermia (40-45°C for up to 1 hour) has been shown useful as an adjuvant. It induces a multitude of changes to the physiology and biology of the target tumor that improve the effectiveness of other treatments and make mild hyperthermia synergistic with many chemotherapeutic agents and radiation therapies. Many currently available devices, including but not limited to radiofrequency (RF) applicators, microwave applicators, hot water baths, lasers, and magnetic fluids, can heat the target tissue to the mild hyperthermic range. However, these suffer from drawbacks: limited or superficial heating, hot and cold spots,...
OncologyCardiometabolicCell/Gene TherapyDrug DeliveryAI / ML
The promise of RNA interference based therapeutics is made evident by the recent surge of biotechnological drug companies that pursue such therapies and their progression into human clinical trials. The present invention discloses novel RNA and RNA/DNA nanoparticles including multiple siRNAs, RNA aptamers, fluorescent dyes, and proteins. These RNA nanoparticles are useful for various nanotechnological applications. This technology has a higher detection sensitivity and higher silencing efficiencies of targeted genes than conventional siRNAs. This technology has significant therapeutic potential against multiple disease types, including, cancer and viral infections. Xxenograft mouse models indicated uptake of the nanoparticles, and six different HIV targets were validated with cell cultures. Competitive Advantages: Potential for higher sensitivity, higher efficiency, low cytotoxicity, multiple functionality, multiple targets, and...
CDC scientists have developed multiple antigenic peptide immunoassays for the detection of human immunodeficiency virus (HIV) and/or simian immunodeficiency virus (SIV). HIV can be subdivided into two major types, HIV-1 and HIV-2, both of which are believed to have originated as result of zoonotic transmission. Humans are increasingly exposed to many different SIVs by wild primates. For example, human exposure to SIVs frequently occurs as a consequence of the bush meat hunting and butchering trade in Africa. Human exposure to SIVs may lead, or may have already led, to transmission of SIVs with potential for new virus induced immunodeficiency epidemics. Unfortunately, new cases of zoonotic virus transmission may go undetected because of the lack of SIV-specific tests. Thus, there is the potential to compromise the safety of the blood donor supply system and seed a new HIV-like epidemic. This invention addresses these problems by...
CDC researchers have developed a bead-based nucleic acid assay for serotyping members of the Salmonella genus; this assay will identify serotypes for approximately 95% of all human-obtained Salmonella isolates in the United States. Presently, production and quality control for the more than 250 antisera required to cover the >2,500 known serotypes using current methods is difficult, expensive and laborious. Many clinical Salmonella isolates can require three to five days to determine serotype, delaying conclusive serotype identification and postponing alerts to public health monitoring programs. To that end, this new assay provides improved diagnostic identification and discrimination as well as reducing reagent consumption and technician labor. The assay has been developed and optimized in parallel with traditional serotyping methods on a panel of 368 isolates that represents all subspecies/serogroup combinations in the current...
CDC researchers have developed a multiplexed diagnostic assay for sensitive detection and distinction between viral group members based on the presence/absence of infection-generated antibodies within a clinical serum sample. For example, this assay can be used for rapid discrimination of a clinical unknown as specifically a West Nile or St. Louis encephalitis viral infection. This is particularly beneficial as these two viruses are typically difficult to distinguish by standard serological assays. This new technique uses microsphere/microbead-based flow-analysis as a platform. Because of a basis in a pre-existing technology, the technique can be easily incorporated into current state and health department diagnostic testing protocols. The method is particularly unique because the assay-generated data can be standardized and then classified via discriminant analysis to determine the presence or absence of antibodies of interest within...
OphthalmologyOncologyInfectious DiseaseImmunologyCardiometabolicInflammationBiologicDiagnostic / BiomarkerAI / ML
It is estimated that over 40 percent of the adult population in the United States has periodontal disease in one form or another. Periodontal Disease is a chronic infection of the periodontal ligament (PDL) and the adjacent bone and cementum. The effects of Periodontal Disease range from simple gum inflammation to, in extreme cases, tooth loss. The NIH announces a new technology wherein stem cells from the PDL have been isolated from adult human PDL. These cells are capable of forming cementum and PDL in immunocompromised mice. In cell culture, PDL stem cells differentiate into collagen fiber forming cells (fibroblasts), cementoblasts, and adipocytes. It is anticipated that these PDL stem cells will be useful for periodontal tissue regeneration to treat periodontal disease. Source institute: NIDCR. Inventors: Shi, Songtao.
An RNA transfection and protein expression approach comprising lipid nanoparticles, hyaluronic acid, and photostimulation Problem: As the field of cell modification has expanded, researchers have sought more effective methods for nucleic acid (NA) delivery into cells. RNA transfection is easier to facilitate and control than DNA transfection, making it a promising candidate for cells to build specific proteins. Researchers have developed various approaches to RNA transfection, such as the use of chemicals, lipid nanoparticles (LNP), electroporation, and phototransfection, but many of these are toxic and/or inefficient. ~99% of gene medicines never reach the target, and for cancer only ~0.7% reaches the tumor. Only 0.007% of gene medicines have an effective therapeutic delivery method. Solution: The inventors have developed an approach to transfection utilizing the combined benefits of LNPs, hyaluronic acid (HA) of different sizes, and...
Tailorable multivalent therapeutic for targeting difficult protein-protein interaction (PPI) interfaces in the context of cancer and infectious diseases
This CDC-developed invention pertains to multivalent antigenic peptides (MAPs) that can be used in a variety of HIV/AIDS diagnostics. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is subdivided into groups M, N, and O, while HIV-2 is subdivided into subtypes A and B. Within HIV -1 group M, several different subtypes and numerous forms of recombinant viruses exist. To detect all types, groups, and subtypes of HIV by serological methods, a mixture of antigens derived from different viral strains representing different HIV types and subtypes is needed. However, due to the competition and dilution effect, mixing multiple antigens may reduce the amount of individual antigen bound to the solid phase and lead to a reduction in assay sensitivity. It is known that MAPs, which contain multiple branches of an oligopeptide sequence, are more antigenic than the corresponding single chain linear peptides. The MAPs encompassed by this...
The nucleotide-binding oligomerization domain 2 (NOD2) protein plays a key role in innate immunity as a sensor of muramyl dipeptide (MDP), a breakdown product of bacterial peptidoglycan. Bacterial peptidoglycan promotes the innate immune response through the activation of Toll-like receptor 2 (TLR2), which ultimately provokes inflammation. Activation of NOD2 by MDP negatively regulates the activity of TLR2, and thus reduces inflammation. The inventors have demonstrated that administration of MDP prevents the development of experimental colitis in mice. They have also determined that MDP reduces pro-inflammatory cytokine production from multiple Toll-like receptors, and that this reduction arises from the induction of IFN regulatory factor 4 (IRF4). The technology includes methods of treating or preventing inflammation associated with an autoimmune disorder, particularly inflammatory bowel disease, via administration of muramyl...
Available for licensing through a Biological Materials License Agreement are the murine MAbs described in Beeler et al, "Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: effect of mutation upon fusion function," J Virol. 1989 Jul;63(7):2941-2950 ( PubMed abs ). The MAbs that are available for licensing are the following: 1129, 1153, 1142, 1200, 1214, 1237, 1112, 1269, and 1243. One of these MAbs, 1129, is the basis for a humanized murine MAb (see U.S. Patent 5,824,307 to humanized 1129 owned by MedImmune, Inc.), recently approved for marketing in the United States. MAbs in the panel reported by Beeler et al. have been shown to be effective therapeutically when administered into the lungs of cotton rats by small-particle aerosol. Among these MAbs several exhibited a high affinity (approximately 10 9 M -1 ) for the RSV F glycoprotein and are directed at epitopes encompassing amino acid 262, 272, 275, 276 or...
This invention concerns "knockout" animals, including mice, which have a deficit of functional steroid hormone receptors, DNA constructs containing the mutations, and methods for producing the animals. The mutation is introduced into the animal or its ancestors at an embryonic stage. These knockout animals provide a model system for studying the biological role of hormones, including steroid hormones and sex steroids, in growth, development, morphological differentiation, and sexual and reproductive behavior and cycles, etc. More specifically, the animals may serve as models for testing sex hormones and synthetics that mimic or antagonize sex hormones for use in birth control methods or as hormone replacement therapies. In addition, they provide a system for the characterization of materials suspected of precipitating or conferring protection against osteoporosis, cardiovascular disease, breast cancer, endometrial cancer, and other...
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammatory disease, and their anti-inflammatory effects are believed to result from their ability to inhibit the formation of prostaglandins by prostaglandin H synthase (COX). Two forms of prostaglandin H have been identified, COX-1 and COX-2. The former seems to be constitutively expressed in a variety of tissues while the high expression of the latter has been reported in colorectal tumors. NSAIDs have been shown to be effective in reducing human colorectal cancers and possibly breast and lung cancers. While the exact mechanism(s) by which NSAIDs function has not been elucidated, they could potentially play a critical role in detecting, diagnosing and treating inflammatory diseases as well as cancer. The present invention relates to screening methods for the identification of agonistic and/or antagonistic agents for the activation of the promoter...
Non-steroidal anti-inflammatory drugs (NSAIDs) have long been used to treat a variety of inflammatory conditions. Many of these conditions, such as cancer or arthritis, require long term use of the NSAIDs due to the chronic nature of the disease. However, the NSAIDs in current use have toxicities associated with their long-term use that hinder their use for these chronic conditions. Researchers at the NCI, in collaboration with Wake Forest University, have developed novel hybrid compounds which combine a NSAID with a nitroxyl (HNO) releasing agent. These modified NSAIDs have significantly reduced toxicity compared to the conventionally used NSAIDs which may allow their administration for the extended periods needed for more chronic conditions without severe side effects. The adverse side effects (i.e. heart attack, thrombosis and severe gut toxicity) observed with conventional NSAIDs are well documented. In fact, some of these drugs...
Summary: Researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development are highly motivated in seeking licensing and/or collaboration partners for the development and use of androgenic compounds as contraceptives and/or hormonal therapeutics. Description of Technology: The available options for male contraceptives are limited. Androgens are administered as part of hormone-based male contraception and have also been used in the treatment of hypogonadism and hormone replacement therapy HRT. Many synthetic androgens require an oil-based delivery vehicle and have limited durations of action. This technology describes androgenic compounds and pharmaceutical compositions thereof for use in a number of diseases or conditions, most notably as a potential male contraceptive, and as an androgenic agent suppressing the release of hormones such as the luteinizing hormone. Additional potential therapeutic areas...
Summary: Researchers at the National Cancer Institute (NCI) seek parties interested in collaborative research and/or licensing to further develop neutralizing nanobodies targeting Lassa virus. Description of Technology: Lassa Hemorrhagic Fever (LHF) is a serious disease caused by infection with Lassa virus (LASV) – highly prevalent in West Africa and spreading globally. LASV is associated with high morbidity and mortality rates, annually infecting 100,000 to 300,000 individuals and causing 5,000 deaths. Developing prophylactics and treatment for LASV is difficult due to challenges in inducing neutralizing antibodies and producing their target, the LASV glycoprotein trimer (GPC). LASV poses a severe public health threat with infections expanding outside the traditional endemic areas and no LHF- specific vaccines or therapies. Researchers at NCI’s Laboratory of Molecular Biology, in collaboration with the Vaccine Research Center at the...
This technology includes a new class of nanobody–antiviral peptide conjugates that block HIV from infecting human CD4⁺ T-cells, positioning them for future therapeutic and prophylactic use. Nanobodies—single-domain antibody fragments—guide the drug to the virus’s docking site and impede receptor binding, while the linked peptide halts the membrane-fusion step, creating a one-two punch against viral entry. In cell-based infection assays the conjugates are markedly more potent than either the peptide alone or a widely used broadly neutralizing anti-HIV antibody, enabling lower dosing and reduced systemic toxicity. Because the construct strikes two independent stages of the viral life-cycle, it raises the genetic barrier to resistance that limits existing treatments. The modular chemistry also allows rapid retargeting to emerging HIV strains or other enveloped viruses. Commercial applications: Long-acting injectable or topical HIV...
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in developed countries. Despite the availability of several synergistic, targeted therapy regiments, the 5-year survival rate for NSCLC is only 15%. The poor prognosis of NSCLS is due in part to limitations of current treatments, which do not trigger an immune response against NSCLC, nor can they be directly delivered into the lungs. Researchers at NCI developed a novel method for synthesizing polyketal nanoparticles with adsorbed CpG oligonucleotides (NP-CpG) that possess immunomodulatory and potent anti-tumor activity, and can be safely delivered to the lungs. The researchers have demonstrated a link between NP-CpG accumulation in pulmonary tumors and an increase in TH1 cells and decrease in Treg cells in vivo . They have optimized particle size for intratracheal delivery, and in vivo studies showed improved efficacy, PK, and PD compared to other CpG...
Mesothelioma is an aggressive cancer covering anatomic surfaces (e.g. lining of the lungs, heart, abdomen, etc.) that resists multi-modality therapies. Regional recurrence of mesothelioma from residual tumor cells prevents long-term benefits after surgical resection. Furthermore, there is no clinical consensus on intracavitary adjuvants that are effective in extending the tumor reduction effect of surgery. Researchers at the National Cancer Institute (NCI) have developed a new technology which fulfills this unmet clinical need by providing a local regional therapeutic platform to shuttle cancer-specific microRNA, thereby circumventing systemic administration challenges. This technology showcases nanoparticles comprised of microRNA bound to disordered peptides that are embedded in a hydrogel engineered from self-assembling β-hairpin peptides. The nanoparticle hydrogel composition is a shear-thinning composite, capable of being...
Problem: Acute ischemic stroke (AIS) is the second leading cause of death worldwide, affecting around 600,000 Americans annually. However, pharmacological treatment of AIS is difficult due to ineffective and nonspecific targeting to blood brain barrier epitopes via intravenous administration. Over 100 drugs have been tried and failed in clinical trials... Problem: Acute ischemic stroke (AIS) is the second leading cause of death worldwide, affecting around 600,000 Americans annually. However, pharmacological treatment of AIS is difficult due to ineffective and nonspecific targeting to blood brain barrier epitopes via intravenous administration. Over 100 drugs have been tried and failed in clinical trials over the past few decades. The leading cause of failure has been the inability to concentrate the drug at the injury site, indicating a strong need for novel delivery and targeting approaches. Solution: The inventors have developed a...
Current treatments for cancer and viral infection are limited remedies that often suppress cell or viral replication rather than eliminate diseased cells entirely from the body. A further limitation is that these therapies often compromise healthy cells as well, leaving problems of recurrence and side effects. Researchers at developed a novel therapeutic nanoparticle (NP) system harboring therapeutic small siRNA that can significantly enhance effectiveness and specificity of treatments by killing diseased cells. Nanoparticles attached to RNA/DNA hybrids encode recognition sites for target genes and partial siRNA sequences of human anti-apoptotic genes. Individually, each of the hybrids is functionally inactive and functional representation can only be activated by the re-association of at least two cognate hybrids simultaneously present in the same cell. Overall, this novel approach allows each NP to have recognition sites for...
Chemotherapy resistance in a wide array of cancers is often associated with enhanced glucose uptake and dysregulation of the insulin signaling pathway. Therapeutics capable of inhibiting insulin signaling would be valuable as a stand-alone treatment and for sensitizing resistant tumors to standard chemotherapy regiments. Researchers at NCI’s Genitourinary Malignancies Branch have synthesized and developed a series of Englerin-A analogues with potent anti-tumor activity that is linked to inhibition of the insulin pathway. The researchers have previously shown that Englerin A has potent activity in vivo using a renal carcinoma xenograft mouse model. A new lead compound with specific activity against renal cell carcinoma, which can be synthesized to scale for in vivo studies, and improved oral bioavailability, has been identified. The NCI seeks partners interested in collaborative research to co-develop this therapeutic with an initial...
Airborne particles can have great impact on air quality, weather, and human health. In particular, long-term inhalation of toxic particulate matter in workplaces could pose a significant health risk. NIOSH scientists have developed a new, low-cost approach based on application of atmospheric radio frequency glow discharge (rf-GD) optical emission spectroscopy for near real-time measurement of elemental concentration in aerosols. The method involves collection of aerosol particles on an electrode tip in a coaxial microelectrode system, followed by excitation of the particles using rf-GD. NIOSH scientists identified far less expensive excitation sources for the rf-GD than traditional spark and laser-based excitation sources. Additionally, these excitation sources are compact and can be miniaturized for development of sensors for personal air sampling. The scientists developed a laboratory instrument, calibrated it for various elements...
This invention describes a general way to trigger the release of a bioactive small molecule from a targeting antibody. The key “trigger” is a fluorescent linker that is chemically disassembled upon irradiation with light in the near-IR range (~800 nm). This linker technology is a dramatic step forward for the field. The molecules can be tracked using conventional fluorescence imaging technology, and with the application of a higher light dose, drug-release can be initiated in a targeted manner. In current clinical practice, a bulk tumor is often removed through a guided surgical approach with the tumor margins cleared by targeted irradiation. This technology promises fewer side-effects and the potential to pre-empt resistance issues by achieving higher, otherwise unattainable, drug doses. Compared to existing photodynamic therapy approaches, this technology relies on the activity of highly potent drug molecules, leading to...
Summary: The NCI seeks parties interested in research co-development and/or licensing of this combination immunotherapy approach of neoantigen-specific T cells administered alongside a neoantigen-targeting vaccine to enhance ACT and treat cancer. Description of Technology: Adoptive cell therapy (ACT) is a breakthrough form of cancer immunotherapy that utilizes autologous, antitumor T cells to attack tumors through recognition of tumor-specific mutations, or neoantigens. A major hurdle in the development of ACT is the exhausted phenotype exhibited by many neoantigen-specific T cells, which limits their efficacy and prevents a sustained immune response. Researchers at the National Cancer Institute (NCI) have developed a combination immunotherapy to rescue the function of exhausted, neoantigen-specific T cells and, thus, enhance ACT. The method involves concurrent administration of neoantigen-specific T cells alongside a vaccine...
The effectiveness of current influenza vaccines varies by strain and season, in part because influenza viruses continuously evolve to evade human immune responses. While the majority of seasonal influenza infections cause relatively mild symptoms, each year influenza virus infections result in over 500,000 hospitalizations in the United States and Europe. Current standard of care for individuals hospitalized with uncomplicated influenza infection is administration of neuraminidase inhibitors. However, frequent use of such antiviral drugs increases the risk that the virus will develop drug resistance, especially in high-risk populations. Thus, alternative strategies are required to protect or treat vulnerable populations who have been hospitalized with severe influenza. Using a combination of recombinant proteins and sophisticated flow cytometry, scientists at NIAID isolated families of antibodies capable of neutralizing diverse group...
Two chimpanzee mAbs specifically reacted with light chain of the botulinum neurotoxin A and neutralize the toxin in the mouse model. They can be used for emergency prophylaxis and treatment of either naturally acquired or terrorist associated botulism. Since the sequence of chimpanzee immune globulin is virtually identical to that of humans, the MAbs are not expected to have problems in repeated administration as equine antibodies. They can also be used for rapid diagnosis of botulinum neurotoxin A. Commercial applications: A research material that can be used in the development of assays, validation of products or in quality control.. Competitive advantages: Speed up product development with NIH developed material that has already been tested and validated.. Source institute: NIAID. Inventors: Purcell, Robert, Emerson, Suzanne, Chen, Zhaochun.
Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia among infants and children under 1 year of age. Illness begins most frequently with fever, runny nose, cough, and sometimes wheezing. During their first RSV infection, between 25% and 40% of infants and young children have signs or symptoms of bronchiolitis or pneumonia, and 0.5% to 2% require hospitalization. Most children recover from illness in 8 to 15 days. The majority of children hospitalized for RSV infection are under 6 months of age. RSV also causes repeated infections throughout life, usually associated with moderate-to-severe cold-like symptoms; however, severe lower respiratory tract disease may occur at any age, especially among the elderly or among those with compromised cardiac, pulmonary, or immune systems. This invention is a human monoclonal antibody fragment (Fab) discovered utilizing phage display technology. The neutralizing...
H7N9 influenza viruses are predominately avian (bird) pathogens, however, since 2013, they have infected more than 1500 humans with a mortality rate of nearly 40% in confirmed cases. H7N9 viruses continue to be a threat to public health. Treatment for people infected with H7N9-subtype influenza A (H7N9) commonly includes the use of drugs that inhibit neuraminidase, a protein found on the virus’ surface. However, like other influenza viruses, H7N9 can become resistant to these drugs. CDC researchers have developed a monoclonal antibody (mAb) that binds to the neuraminidase protein of H7N9 influenza viruses, and has been shown in animal studies to provide protection from H7N9 infection. Because this antibody targets a different region of the neuraminidase protein than other antibodies, it is unlikely that H7N9 strains have developed resistance to it, making it an ideal starting point for antibody-based therapy or prevention of H7N9...
Adoptive cell therapy (ACT) is an attractive new therapeutic approach for treating various cancers. ACT has recently demonstrated a high degree of efficacy when treating patients with hematological malignancies. However, to date, no effective Chimeric Antigen Receptors (CAR) T cell therapy exists for solid tumors. Researchers in the National Cancer Institute (NCI) Laboratory of Molecular Biology (LMB) have created a new CAR format that is available for licensing and further co-development. This new format uses a specific promoter and signal peptide in a specific order allowing for increased efficiency of CAR T therapy. The inventors found that there was an increased therapeutic effect when using their proprietary (anti-glypican 3 [GPC3]) hYP7 antibody in this format. Additionally, the inventors are exploring the use of this new CAR T format in conjunction with other antibodies against multiple other cancer antigens, including...
Recombinant immunotoxins (RITs) constitute a promising solution to hematologic cancers (e.g., Multiple Myeloma [MM]). RITs are chimeric proteins composed of a targeting domain fused to a bacterial toxin. Upon binding to a cancer cell displaying the target antigen, RITs are internalized, metabolized and the released toxin kills the cell. While highly active and effective, current RITs have short half-lives, requiring them to be used in high concentrations for treatment. At such high concentrations, RITs may show nonspecific activity and kill healthy cells. Scientists from the National Cancer Institute’s (NCI) Laboratory of Molecular Biology developed a new class of RITs active in low doses and demonstrating prolonged stability in the body. Specifically, albumin binding domains (ABDs) have been introduced into the toxin portion of the RIT. ABDs allow the RIT to bind to serum albumin – extending the life of the RITs while not interfering...
Summary: The National Institutes of Health is seeking commercial partners to co-develop and/or license a heterocyclic scaffold for development of therapeutics against Plk1-dependent cancers. Description of Technology: Polo-like kinase 1 (Plk1), a member of the Polo-like kinase family, plays a critical role in regulating mitosis and cell cycle progression. Aberrant expression of Plk1 has been observed in a variety of human cancers, and it is known to be associated with tumorigenesis as well as poor prognosis in cancer patients. Unlike normal cells, some cancer cells are dependent on augmented Plk1 levels to remain viable and are killed when Plk1 function is attenuated. Although Plk1 has proven to be an attractive target in cancer treatment, currently available Plk1 inhibitors have shown limited efficacy with significant dose-limiting toxicity and non-specificity in various preclinical or clinical trials. Thus, there remains an unmet...
Modulate oxygen-releasing erythroid progenitor cells (EPCs) to promote low oxygen conditions (hypoxia) and enhance bone fracture repair. Problem: Bone fracture repair (or healing) is a complex regenerative process aimed at restoring damaged bone to its pre-injury state. About 5% to 10% of all fractures experience delayed or failed healing during this process. Previous studies have suggested that the initial phase of the repair process is characterized by a pronounced oxygen insufficiency (low oxygen condition, or hypoxia), attributed to the disruption of blood vessels. However, due to methodological limitations, the oxygenation activities in the fracture gap remain poorly understood. Solution: The inventors employed different methods to study tissue oxygenation in the fracture gap. They observed high oxygen concentrations that may impede repair in the local area days after the fracture. To address this, the inventors showed that...
Technology Overview: This technology provides a novel proton beam profiling technology with excellent spatial and temporal resolution. Proton radiation therapy is becoming widely adopted for cancer treatment due to its capability of producing maximum dosage within an extremely small area and controlled depth in the tissue. In order to controllably... Inventors: Robert Hollebeek.
OncologyCardiometabolicDiagnostic / BiomarkerAI / ML
Technology Overview: Researchers in the Christianson Lab have designed arginase inhibitors that bind to arginase I and II, and conducted structural analyses of several three-dimensional crystal structures with arginase-inhibitor complexes. Inhibiting arginase enhances nitric oxide-dependent smooth muscle relaxation, including gastrointestinal, airway,... Applications: Arginase inhibitors can be used for treatment of asthma/COPD, diabetes, hypertension, and sexual dysfunction Spectroscopic probe when attached to fluorescent molecule or NMR/MRI probe Diagnostic tool for determination of arginase overexpression as associated with asthma, cancer, or bacterial infections (H. pylori) Inventors: David Christianson.
This technology includes a family of small-molecule antagonists that selectively block the 5-HT 2B serotonin receptor—an upstream driver of tissue-remodeling—to address fibrotic, cardiopulmonary and related disorders. Built on a conformationally-locked “(N)-methanocarba” nucleoside scaffold, the compounds show nanomolar potency, >30–400-fold selectivity over the closely related 5-HT 2C receptor, and favorable oral bioavailability in rodents. In vivo mouse studies confirm functional antagonism without central nervous system side-effects, while ADMET profiling indicates metabolic stability and no hERG liability. The result is a drug-like, patent-protected platform ready for lead optimization or IND-enabling studies in lung, liver and cardiac fibrosis, pulmonary arterial hypertension, and other high-value indications. Commercial applications: Disease-modifying treatment for systemic, pulmonary and hepatic fibrosis (e.g., idiopathic...
Nitric oxide (NO) has a broad spectrum of actions in physiological and pathological processes. NO-donor drugs have shown therapeutic effect in several cancer types by inducing apoptosis but the concentrations required have suggested limited clinical applicability. For cancers such as non-small cell lung cancer where most therapies are not curative, there remains a need for effective treatments. Scientists at the National Cancer Institute have identified a diazeniumdiolate-based NO releasing prodrug, JS-36-25, with selective cytotoxicity towards cancer cells. This prodrug has potent tumoristatic activity in lung cancer cells in vitro and in mice xenografts. Treatment with JS-36-25 in vivo led to 85% reduction of tumor growth. The tumoristatic potency of the compound had a negative correlation with the level of endogenous reactive oxygen species (ROS) in the cancer cells. Thus, in addition to potent tumoristatic activity when...
A number of factors can play a detrimental role in the process of wound healing such as poor nutritional status, smoking, various drugs, cancer, and diabetes. Wound healing impairment is a challenging clinical problem with no efficacious treatments currently available. Nitric oxide (NO) has been shown to play a role in the process of wound healing by promoting both the proliferative and remodeling phases of healing. The present invention from NCI's Chemical Biology Laboratory is a polyvinylpyrrolidone (PVP)-based polymer that is capable of releasing NO at therapeutic levels over a prolonged period of time when applied to a moist wound. The polymers can also be incorporated into wound dressing and bandages for enhanced wound healing compared to the bandage alone. These wound dressings and bandages may be useful in the treatment of wounds, various infections and dermatological conditions, and for follow-up to cancer treatments...
Diazeniumdiolates comprise a diverse class of NO-releasing compounds and materials that are known to exhibit sufficient stability to be useful as therapeutics. Diazeniumdiolated compounds have been attached to polymers, substrates, and medical devices for the treatment and management of a variety of diseases including cancer, inflammation, heart disease, and hypertension. Despite the extensive literature available on NO and nitric oxide-releasing compounds, there remains a need for stable nitric oxide-releasing polymers, such as polysaccharides, or small molecules, such as monosaccharides and disaccharides, that exhibit a sustained release of nitric oxide for the treatment of disease. This invention discloses novel materials and a method for producing nitric oxide (NO)-releasing derivatives of any material containing a reducing sugar component. It may be used to produce NO-releasing cotton bandages or surgical fabrics, cellulose...
Cell-free hemoglobin based oxygen carriers (HBOCs) are blood substitutes and resuscitative agents that can be used to replace whole blood donations, alleviate blood shortages and reduce the risks of infections such as HIV and hepatitis. Stroma-free HBOCs offer the advantages of increased stability, consistency of supply, and reduced immunogenicity over the use of the alternative cell based sources. However, the side effects associated with their use, including vascular toxicity, pulmonary and systemic hypertension, myocardial infarction, inflammation, and platelet aggregation severely limit their scope of clinical applications. These adverse effects are due in part to the ability of free deoxygenated hemoglobin (deoxyHb) to scavenge for nitric oxide (NO) thus rendering it unavailable for vasodilating blood vessels. This technology is a method of using nitrites to reduce the deleterious effects associated with HBOC use as blood...
Synthetic antimicrobial peptides derived from wasp venom to treat antibiotic-resistant infections. Problem: Antibiotics have transformed modern medicine as they are just one of the most effective drugs in history. However, the rise of antimicrobial resistance (AMR) currently threatens to undermine these achievements, posing a major threat to public health. Millions of patients worldwide, including tens of thousands in the US, die each year from untreatable infections due to the emergence and spread of antibiotic resistance while the arsenal of effective drugs shrinks. As a result, the market for these drugs is set to grow 3-7% until 2030. Venoms represent an underexplored potential source of new antibiotics; however, they are limited by their toxicity. Solution: Here, rationally designed, synthetic variants of two natural or wild-type (WT) antimicrobial peptides (AMPs) found in Eumenes micado wasp venom are non-toxic against human...
Fluorescently labeled α-synuclein to examine destabilization of synuclein fibrils by small molecules and therapeutics for neurodegenerative diseases Problem: Misfolding of the neuronal protein α-synuclein triggers oligomerization and the formation of amyloid fibrils that are the pathological hallmarks of Parkinson’s disease. The molecular mechanism of synuclein misfolding has not been elucidated, and therefore, screening of compounds that block or reverse aggregation can establish novel mechanisms of action. Previous efforts to employ small molecule probes, such as Thioflavin T and Congo Red, in drug screening experiments have been unfavorable, as the probes compete with candidate compounds for binding sites on synuclein. There is no cure for these progressive neurodegenerative diseases, although therapeutics and biologics are in development. A high-throughput screening method to examine fibril disaggregation as a measure of...
This CDC developed invention is a novel device for a miniature, nonradioactive bipolar charger to electrically charge aerosol particles for use in personal and portable aerosol instrumentation. Such devices are an integral component of aerosol instruments employing electrical mobility-based techniques. Current, commercial state-of-the-art mobility instruments employ aerosol chargers using radioactivity to achieve bipolar particle charging and, therefore, are not suitable for field-portable instruments. Due to strict regulatory restrictions on use of radioactive materials, these radioactive chargers also tend to be too bulky for use in compact aerosolization instruments. This invention circumvents these two critical drawbacks by eliminating radioactivity and miniaturizing overall unit size (1x0.75 x 0.5 inch). Other unique aspects of the invention entail elimination of the need for additional air flows (other than the aerosol sample...
Available for licensing are novel pyrrolopyrimidine compounds that disrupt the assembly of the perinucleolar compartment (PNC), a sub-nuclear structure highly prevalent in metastatic tumors. These notable compounds act without overt cytotoxicity. The presence of the PNC positively correlates with metastatic capacity, making it a potential marker for cancer development and prognosis. These compounds could also serve as useful tools to elucidate the biology driving the formation and maintenance of the PNC, and unravel its association with metastasis. Commercial applications: Use in the therapeutic intervention of metastasis in cancer. Use as tools to elucidate the biology of the PNC. Competitive advantages: No existing FDA-approved treatment for the clinical management of metastasis. Target is specific to metastatic tumors. Compounds are not toxic. Broadly acting across all metastatic cancers. Source institute: NCATS. Inventors:...
Inhibitors and tools to block the local formation of steroid hormones in hormone-dependent malignancies of the prostate, breast and endometrium Problem: Standard treatment of care for hormone-dependent tumors utilizes hormone ablative therapies. These agents non-discriminately block the action of estrogens and androgens and have untoward side effects. Additionally, patients develop resistance to these agents quite frequently. Dr. Penning has identified enzymes that belong to the aldo-keto reductase (AKR) superfamily that are required for hormone synthesis in a tumor-specific manner. His lab has developed AKR inhibitors that could block steroid hormone synthesis within these tumors with precision. Solution: As proof-of-principle Dr. Penning has focused attention on castration resistant prostate cancer (CRPC). CRPC is uniformly fatal and accounts for 30,000 deaths annually in the US alone. Advanced prostate cancer is treated with...
This invention provides a novel family of acylthiols and uses thereof. More specifically, this invention provides effective inhibitors of HIV that selectively target its highly conserved nucleocapsid protein (NCp7) by interacting with metal chelating structures of a zinc finger-containing protein. Because of the mutationally intolerant nature of NCp7, drug resistance is much less likely to occur with compounds attacking this target. In addition, these drugs should inactivate all types and strains of HIV and could also inactivate other retroviruses, since most retroviruses share one or two highly conserved zinc fingers that have the CCHC motif of the HIV Ncp7. Finally, this invention could be very useful for the large-scale practical synthesis of HIV inhibitors, because these compounds can be prepared by using inexpensive starting materials and facile reactions. Thus, it opens the possibility that an effective drug treatment for HIV...
The subject invention describes a new class of compounds (such as peptides or mimetics) that target viral RNAs and inhibit the viral life cycle by blocking the viral recognition process. More specifically, these compounds are the first against an RNA Target - currently there are no clinical drugs against RNA targets in the treatment of any type of human disease. Anti-HIV drugs currently on the market are complicated by the development of resistance and substantial side-effects; however, these compounds would unlikely develop any side effects because of their very high specificity against only viral RNA. In addition, these compounds may be further linked to a detectable label. Thus, these compounds have the potential to be used as a new class of systemic drugs for the treatment of HIV infection and to be developed into diagnostic kits or devices. Competitive Advantages: New class of compound. Inhibits the viral recognition process and...
Scientists at the National Cancer Institute's Molecular Targets Laboratory have discovered that Cnidarins as a novel class of highly potent proteins capable of blocking the HIV virus from penetrating T-cells. Cnidarins were found in a soft coral collected in waters off Australia's northern coast. Cnidarins can block virus fusion/entry but do not block viral attachment. In addition, Cnidarins do not have lectin-like activity and therefore possibly a unique mechanism of action. Thus, Cnidarins may represent important new leads for HIV microbicides or for systemic therapeutics for HIV. Competitive Advantages: High potency against HIV. Novel Chemical composition. Family of related proteins. Unique mechanism of action. Commercial Applications: Microbicide, Therapeutic, Research tool Source institute: NCI. Inventors: O'Keefe, Barry, McMahon, James, Ramessar, Koreen, Xiong, Chang-yun.
This invention describes a new vaccine against Strongyoides stercoralis , which establishes a parasitic infection that affects an estimated 100-200 million people worldwide. The potential for fatal disease associated with S. stercoralis infection and the difficulty in treating hyperinfection underscores the need for prophylactic vaccines against the disease. This vaccine uses S. stercoralis immunoreactive antigen (SsIR); a novel antigen capable of providing 70-90 % protection for mice immunized with the antigen. In addition, sera from immunized mice have also been used to effectively protect naive mice from infection. The invention may also have potential use in diminishing allergic responses, as Strongyoides stercoralis infection has been shown to reduce the murine response to allergens. Consequently, SsIR may be used to immunize individuals and reduce the allergic response. The antigen may also be used to identify homologous...
This technology includes a new class of synthetic peptides that activate Lipoprotein Lipase (LPL), a key plasma enzyme that lowers triglycerides. Mutations in apoC-II is a genetic cause of severe hypertriglyceridemia, which can lead to cardiovascular disease and pancreatitis. The last helical domain (3rd helix) of apoC-ll activates LPL, and we discovered by making a series of amino acids substitutions in the second helix to increase its ability to bind to lipoproteins that we were able to produce novel apoC-II mimetic peptides that potently activate LPL and are less likely to be immunogenic. Commercial applications: Treatment of apoC-11 deficiency and hypertriglyceridemia. Competitive advantages: There is currently no known therapy for apoC-11 deficiency. Source institute: NHLBI. Inventors: Ghosh, Soumitra, Lo, Chih-Hung, Remaley, Alan, Sviridov, Denis.
There are no analgesics to ameliorate chronic pain without adverse side-effects (e.g., respiratory depression, gastrointestinal effects, tolerance, dependence), thus forcing patients into a difficult choice of negative impacts on quality of life. Most of the analgesics used for chronic and acute pain are drugs such as oxycodone, morphine, oxymorphone, and codeine. All of these opioids have been subject to misuse; prescription drug abuse is a severe problem worldwide, causing high mortality and greatly increased emergency room visits. Recently, research indicated that the analgesic and side-effects of opioids may be separable. Initial work in 1999 by Bohn et al. using -arrestin 2 knockout mice showed that antinociception was enhanced when morphine could not recruit -arrestin. During the next 19 years, Bohn and others showed that the unwanted side-effects of morphine, and presumably all of the classical opioids, such as respiratory...
Biologic therapeutic approach to modulating T cell inflammatory diseases by expressing isolated or recombinant combinations of WSX-1 or gp130 polypeptide with interacting proteins (such as p28, EBI3, Il-27) to inhibit pathological T cell development. Problem: The interleukin-27 receptor (WSX -1) is a heterodimeric type I cytokine receptor for interleukin-27 comprising the WSX-1 (alpha subunit) and glycoprotein 130 and is essential for initiation of Th1 cell differentiation. Solution: Dr. Christopher Hunter discovered that WSX-1 signaling has a negative effect on T cell responses. In fact, a WSX-1 fusion protein or soluble p28 (Il-30) is able to enhance the ability of Il-27 to inhibit T cell production of Il-2 and IFNγ as well as the T cell subset of Il-17 producing T cells, which is a major pathological T cell subset. Penn has pending proprietary rights to various polypeptide compositions which encompass this technology. Inventors:...
Several malignancies associated with a poor prognosis such as lung, pancreatic and colorectal cancers frequently harbor constitutively active KRAS mutants, which play a pivotal role in oncogenesis. Currently, there are no potentially curative treatments against most mutant KRAS harboring cancers once they become metastatic and unresectable. Despite intensive efforts to develop potent mutant KRAS inhibitors, none have shown a significant improvement to patients. Researchers at NCI’s Surgery Branch have used their expertise in T-cell based therapies to develop a T cell receptor (TCR) that specifically recognizes G12D KRAS, a common driver of oncogenesis. This invention offers an alternative therapy to direct inhibition of mutant KRAS that has been demonstrative to be an effective treatment for advanced melanoma, lymphoma and sarcomas. The inventors have demonstrated that lymphocytes expressing the engineered TCR selectively target...
Description of Technology: Cancer is one of the leading causes of death in United States and it is estimated that there will be more than half a million deaths caused by cancer in 2009. A major drawback of the current chemotherapy-based therapeutics is the cytotoxic side-effects associated with them. Thus there is a dire need to develop new therapeutic strategies with fewer side-effects. Immunotherapy has taken a lead among the new therapeutic approaches. Enhancing the innate immune response of an individual has been a key approach for the treatment against different diseases such as cancer and infectious diseases. This technology involves the generation of novel chemoattractant toxins that deplete the T regulatory cells (Treg) or other immunosuppressive or hyperactivated cells locally. Treg controls activation of immune responses by suppressing the induction of adaptive immune responses, particularly T cell responses....
Novel compounds allowing for optical detection and targeting of Choline Kinases for cancer treatment. Problem: Choline Kinase (ChoK) deregulation is associated with oncogenesis and tumor progression in a number of human cancers, including glioblastoma, breast, and lung cancers. In breast cancer, elevated ChoK activity is correlated with histological tumor grade, resistance to antiestrogen therapies, and poor prognosis. Overexpression of ChoK alone is sufficient to induce malignant transformation. Solution: The Delikatny Lab at the University of Pennsylvania has developed and synthetized novel cancer theranostics – therapeutics that can also serve as diagnostics – molecules based on ChoK Inhibitors. These small fluorescent molecules used at low doses can be effective as agents to image the status of tumor choline metabolism, at higher doses they can serve as inhibitors of tumor growth. Applications: Diagnostic: fluorescent detection of...
Method allowing to increase sensitivity and/or overcome resistance to EGFR inhibitors in cancer cells through inhibition of palmitoyltransferase DHHC20. Problem: Inappropriate activation of the epidermal growth factor receptor (EGFR) contributes to a variety of human malignancies and correlates with poor prognosis and resistance to therapy. Whereas therapy targeting EGFR is currently approved for non-small cell lung carcinomas (NSCLC), advanced colorectal cancer, glioma, pancreatic carcinoma and head and neck tumors; triple negative breast cancer and NSCLC often show resistance to currently available therapies. Solution: Dr. Eric Witze’s lab at Penn has found that inhibition of palmitoyltransferase DHHC20 in cancer cells creates a dependence on EGFR signaling for cancer cell survival. Using a palmitoyltransferase inhibitor researchers demonstrated increased sensitivity to Gefitinib in EGFR-activated cancer cells as well as reversal of...
CDC researchers have characterized epitopes of Bacillus anthracis Lethal Factor (LF), a critical component of the B. anthracis lethal toxin. These epitopes may allow for development of therapeutics for the treatment or prevention of B. anthracis infection. They may also allow screening for B. anthracis LF in a sample and development of a peptide anthrax vaccine. Commercial applications: Diagnostic tests assessing active Lethal Factor in a sample. Anthrax neutralizing therapeutics and vaccines for B. anthracis . Biodefense, biosecurity. Competitive advantages: Potentially faster, lower-input assay compared to current Edema Factor detection methods. Easily adaptable for high-throughput screening of numerous specimens. Source institute: CDC. Inventors: Bagarozzi, Dennis, Boyer, Anne, Quinn, Conrad, Goldstein, Jason.
Ebola Virus Disease (EVD) is a disease caused by infection with viruses from the family Filoviridae , genus Ebolavirus . Ebola virus was first discovered in 1976 in Africa and has since caused numerous outbreaks throughout the continent including the largest outbreak in history in West Africa during 2014-2016. Previously, there were three identified Ebolavirus species which were known to cause disease in humans: Ebola virus ( Zaire ebolavirus ); Sudan virus ( Sudan ebolavirus ); and Tai Forest virus ( Tai Forest ebolavirus ). CDC discovered a fourth novel virus, first identified in Uganda, Bundibugyo virus ( Bundibugyo ebolavirus ). This virus species is significantly different from other ebolaviruses previously identified, therefore, current genetic-based (RT-PCR) assays may fail. CDC’s technology includes compositions and methods for nucleic and immunological protection from, detection of, and treatment of EVD caused by Bundibugyo...
Summary: The National Cancer Institute (NCI) seeks licensees for a family of novel furoquinolinedione derivatives that inhibit tyrosyl-DNA phosphodiesterase 2 (TDP2) as cancer therapeutics. Description of Technology: Tyrosyl-DNA phosphodiesterase 2 (TDP2) is an enzyme that plays a critical role in repairing nucleic acid lesions, namely by repairing trapped DNA cleavage complexes. TDP2 repairs topoisomerase (TOP2)-mediated DNA damage induced by chemotherapeutic agents and removes endogenous TOP2-DNA cleavage complexes. Further, TDP2 deficiency potentiates the antiproliferative activity of TOP2 inhibitors. This suggest that combination therapies consisting of TDP2 and TOP2 inhibitors have a synergistic effect on tumor tissues. Therefore, TDP2 represents a promising anti-cancer pharmacological target as a monotherapy or part of a combination therapy. The NCI investigators and their collaborators have discovered a series of novel...
Research and development leading to the discovery of novel antibiotics has waned in recent years. At the same time, the emergence and spread of antimicrobial resistance has compounded the global danger to human health from bacterial infections. The bacterial protein 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthetic pathway. This pathway is essential for bacteria and microorganisms but is absent in mammals – making it an attractive target for antibiotics. HPPK is a novel target for antibiotics as none of the antimicrobial agents currently on the market or in later stage development are HPPK inhibitors. Researchers at the NCI have developed several novel small-molecule inhibitors directed against HPPK for potential use as antimicrobial agents. The compounds described in this invention present strong binding affinity for HPPK with Kd values as low as 50 nM. The NCI seeks co-development...
Summary: The NIA seeks co-development partners and/or licensees for the further development of Cα-peptide as a therapeutic that inhibits islet amyloidosis. Description of Technology: Over 32 million Americans are living with Diabetes and newly diagnosed cases of type 1 and type 2 diabetes is increasing. A defining feature of type 2 diabetes mellitus (T2DM) is the accumulation of islet amyloid polypeptide (IAPP) fibrils in pancreatic islets. Such accumulations form amyloid plaques, referred to as islet amyloidosis. Mounting evidence suggests that islet amyloidosis plays a causative role in the development and progression of ß-cell dysfunction in T2DM. Currently, approved therapies for T2DM modulate the production of or sensitivity to insulin, but do not specifically target islet amyloidosis. Thus, there is an unmet need to develop new diabetes treatments that inhibit islet amyloidosis. Additionally, any therapy preventing IAPP...
Description of Technology: Over 34 million Americans are living with diabetes. An estimated 6.5 million Americans are living with Alzheimer’s disease (AD) and type 2 diabetes mellites (T2DM). Amyloidosis due to aggregation of amyloid-β is key pathogenic event in AD, whereas aggregation of mature islet amyloid polypeptide (IAPP37) in human islet leads to β-cell dysfunction. A hallmark feature of T2DM is the accumulation of islet amyloid polypeptide fibrils in pancreatic islets. Such accumulations form amyloid plaques and cause apoptosis of -cells of islets. Researchers at NIA used a bioinformatic and molecular biological approaches to identify two novel islet amyloid polypeptide isoforms: IAPPβ, encoding an elongated propeptide of the conventional IAPP and a non-aggregating IAPPγ, which is processed to an unrelated mature IAPP25 instead of IAPP37. They developed a quantitative selective reaction monitoring (SRM) proteomic assay that...
Scientists at the NCI's Surgery Branch have developed anti-CD70 chimeric antigen receptors (CARs) to treat cancers. CD70 is an antigen that is expressed on a variety of human cancers such as renal cell carcinoma, glioblastoma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. The anti-CD70 CARs are hybrid proteins consisting of a receptor portion that recognizes CD70 antigen, and intracellular T cell signaling domains selected to optimally activate the CAR expressing T cells. Genetically engineered T cells that express this CARs will bind to CD70 on the cancer cells and will be activated to induce an immune response that promotes robust tumor cell elimination when infused into cancer patients. This technology can rapidly generate a vigorous T-cell response from the patient's own blood, targeting CD70 expressing cancer cells, and potentially induce tumor rejection. Competitive Advantages: CD70-specific CARs expressed on T cells...
Novel derivatives of oleic acid effectively inhibiting ferroptosis that could be used for treatment of Friedreich Ataxia, neurodegenerative diseases, and neuropsychiatric diseases. Problem: Ferroptosis is a non-apoptotic form of cell death characterized by the iron-dependent accumulation of toxic lipid-reactive oxygen species. Ferroptosis has been suggested to be the main driver of neurological cell death in diseases such as Parkinson's disease, Alzheimer disease, and Huntington's disease as well as in neuropsychiatric conditions such as bipolar disorder, schizophrenia, and depression. In addition, previous studies from Dr. Wilson’s lab showed that Friedreich ataxia (FRDA), an inherited neurodegenerative disorder, may involve ferroptosis in its pathogenesis ( Cotticelli et al., 2019 ). Thus, the development of novel ferroptosis inhibitors is currently considered a promising avenue for treatment of neurodegenerative and...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for a class of novel aplithianine-derived small molecule analogs that compete with ATP for binding on a range of clinically relevant kinases including: Oncogenic gene fusion DNAJB1-PRKACA (PKADJ). Wild type protein kinase A (PKA) . Protein kinase G (PKG). Ccdc2-like kinases (CLK) 1 & 2. DYRK family of kinases. Description of Technology: In 2022, the NCI Molecular Targets Program (MTP) completed a screen of ~150,000 pre-fractionated natural products from the NCI Program for Natural Product Discovery (NPNPD). From this screen, a class of active compounds, named Aplithianines A & B (isolated from the marine organism Aplidium sp.), showed broad potential applicability to numerous kinases of importance including but not limited to: Oncogenic gene fusion DNAJB1-PRKACA (PKADJ) Implicated in an ultra-rare adolescent liver cancer. . Wild type...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for a class of novel aplithianine-derived small molecule analogs that compete with ATP for binding on a range of clinically relevant kinases including: Oncogenic gene fusion DNAJB1-PRKACA (PKADJ). Wild type protein kinase A (PKA) . Protein kinase G (PKG). Ccdc2-like kinases (CLK) 1 & 2. DYRK family of kinases. Description of Technology: In 2022, the NCI Molecular Targets Program (MTP) completed a screen of ~150,000 pre-fractionated natural products from the NCI Program for Natural Product Discovery (NPNPD). From this screen, a class of active compounds, named Aplithianines A & B (isolated from the marine organism Aplidium sp.), showed broad potential applicability to numerous kinases of importance including, but not limited to: Oncogenic gene fusion DNAJB1-PRKACA (PKADJ) Implicated in an ultra-rare adolescent liver cancer. . Wild type...
Novel peptides for treating conditions or diseases resulting from dysregulation in the immune system, such as septic shock, wound healing and autoimmune diseases.
A primary goal of diabetes therapy is to improve control of blood glucose levels (known as glycemic control) in patients. Prospective studies of both Type 1 and Type 2 diabetes indicate that careful glycemic control significantly reduces the risk of microvascular, neurological, and cardiovascular complications of diabetes. The current method of monitoring glycemic control involves measuring levels of the intracellular hemoglobin (HbA1C). However, levels of HbA1C reflect glycemic control over a timeframe of several months and are susceptible to a variety of perturbing factors such as hematologic disorders, kidney disease, aspirin or penicillin use, or alcohol intake. This technology describes a family of novel glycated peptide and protein biomarkers for glycemic control, as well as a method to monitor glycemic control in diabetic patients. In contrast to intracellular HbA1C, this technology detects glycated plasma proteins, which may...
The occurrence of thyroid cancer has been increasing in the United States. For some patients, with particularly advanced and metastatic cancer, current treatments such as thyroidectomy and adjuvant radioactive iodine therapy can lead to poor outcomes. Hence, there is a need for new thyroid cancer treatments. Researchers at the NCI have developed novel T-cell receptors (TCRs) to target thyroid cancer. They immunized HLA-A2+ transgenic mice to generate TCRs that recognize human thyroglobulin (TG). TG, a tissue-differentiation antigen, is only expressed in thyroid cancer and normal thyroid tissues. The anti-TG TCRs can be expressed in a patient’s peripheral blood lymphocytes as part of adoptive cell therapy (ACT) to treat cancer. This discovery, along with hormonal therapy to replace normal thyroid function, can be used to eradicate tumor cells. The National Cancer Institute, Surgery Branch , is seeking statements of capability or...
This CDC developed Limiting-Antigen avidity Enzyme Immunoassay (LAg-avidity-EIA) provides an easy way to measure increasing binding strength (avidity) of HIV antibodies as part of maturation HIV antibodies after seroconversion, providing a method to distinguish early-stage from long-term HIV-1 infection. Surveillance of HIV-1 provides information on prevalence rates of the disease, but determination of new infection rates (HIV-1 incidence) is difficult to deduce. Longitudinal follow up is expensive and can be biased. Unlike assays which use antigens derived from only one subtype and use two wells, this new approach employs a multi-subtype recombinant protein, rIDR-M, to permit equivalent detection of antibody avidity among different subtypes, and measures binding strength of antibody in one well. This assay will allow the simultaneous testing of more specimens and better overall reproducibility due to its design. Further, the approach...
Streptococcus pneumoniae ( S. pneumonia ), bacteria commonly referred to as pneumococcus, are a significant cause of disease resulting in 1.5 million deaths every year worldwide according to the World Health Organization. The major types of pneumococcal disease are pneumonia (lung infection), bacteremia (bloodstream infection), and meningitis (infection of the tissue covering of the brain and spinal cord). Less severe pneumococcal illnesses include ear and sinus infections. CDC scientists have developed a specific amino acid sequence, the P4 peptide, of the Pneumococcal surface adhesin A (PsaA) protein which is an immunogenic epitope and a binding site for adhesion of Streptococcus pneumoniae to human cells. This novel peptide and related sequences, monoclonal antibodies, and uses thereof can be used for vaccine development. Successful polysaccharide vaccines are available in the US, however, countries with limited resources cannot...
CDC researchers have isolated and characterized the novel primate T-lymphotropic viruses denoted human T-lymphotropic viruses 3 and 4 (HTLV-3 and HTLV4), that are believed to have resulted from cross-species transmission at some point in the past. It has been previously established that HTLV-1 causes adult T cell leukemia and other inflammatory diseases; HTLV-2 is considered less pathogenic than HTLV-1 and has been associated with a neurologic disease similar to HTLV-1-associated myelopathy. At present, the human pathologies of HTLV-3 and HTLV-4 are yet uncharacterized, but have been identified as infecting rural Central African hunters who have much greater risk of contact with non-human primates, sometimes infected with simian T-lymphotropic viruses (STLVs). As HTLV infected individuals from rural, isolated populations have increasing contact with their urban brethren, there is increased potential for the rapid spread of new viral...
Brain penetrating compounds as promising therapeutics for treatment of neurodegenerative disorders. Problem: An estimated 6.2 million Americans live with Alzheimer’s Disease (AD), and this number is projected to reach over 13 million by 2050 with societal costs expected to rise to $1.1 trillion. A key feature of AD-affected brain tissue is the presence of insoluble tangles within neurons, leading to their dysfunction and subsequent death. These tangles are comprised of tau protein, which is normally responsible for stabilizing microtubules that are critical to normal neuronal function. However, in AD and related neurodegenerative diseases tau dissociates from microtubules, which compromises microtubule function and facilitates tangle formation. Solution: Compounds that cross the blood-brain barrier and stabilize microtubules can normalize microtubule function in AD and related diseases. Such compounds from the triazolopyrimidine...
This invention relates to recombinant Rift Valley fever (RVF) viruses containing deletions in one or more virulence genes. The recombinant RVF viruses, generated using a plasmid-based reverse genetics system, can be used as vaccines to prevent RVF infection in livestock and humans. The recombinant RVF viruses grow to high titers, provide protective immunity following a single injection, and allow for the differentiation between vaccinated animals and animals infected with wild-type RVF virus. Additionally, this technology relates to a method of using reverse genetics to generate recombinant RVF viruses. Commercial applications: Rift Valley fever (RVF) virus vaccine development or improvement. Prevention of RVF virus infection in livestock and humans. Biodefense, biosecurity. Competitive advantages: In vivo evidence shows single-dose protection. Allows for discrimination between vaccinated and naturally-infected subjects. Useful for...
The catalytic subunit of the DNA-dependent protein kinase complex (DNA-PKcs) has been shown to be important in DNA repair and VDJ recombination in lymphocytes. The inventors have discovered that DNA-PKcs also plays novel, important roles in energy regulation and neurological function. The inventors observed that mature DNA-PKcs-deficient mice (also known as SCID mice) have a lower proportion of fat, resist obesity, and have significantly greater physical endurance than wild-type control mice, particularly with increasing age. The inventors also observed that DNA-PKcs-deficient mice have better memory and less anxiety. One potential explanation for this is that they express higher levels of brain-derived neurotrophic factor (BDNF), which is associated with neurogenesis, memory formation and suppression of anxiety and depression. Moreover, DNA-PKcs-deficient cells produce less oxidative stress. Thus, inhibition of DNA-PKcs may have...
The transmission of malaria begins with injection of sporozoites into a human from the bite of a female anopheles mosquito, which initiates the malarial life cycle in humans. When a mosquito bites an infected human, the ingested male and female malaria gametocytes fuse to form a zygote that eventually becomes an oocyst. Each oocyst produces thousands of sporozoites which migrate to the mosquito salivary glands, ready to infect a new human host. Currently, the available therapeutics for malaria can effectively eliminate the asexual stages of malarial parasites that cause clinical symptoms in patients. However, their abilities to eliminate the gametocyte (sexual stage of the parasites) as well as the liver stage parasites are limited. The subject technology involves novel compounds, which include Torin 2, that are potently gametocytocidal in in vitro assays and in a mouse model of malaria, completely blocked the host-to-mosquito...
This technology is a collection of small molecules screened for their ability to prevent or reduce the cytotoxic effects of the protein, Huntingtin. Huntington's disease is a neurodegenerative disorder due to a dominantly acting expansion of a CAG trinucleotide repeat in exon 1 of the Huntington ( HTT ) gene resulting in production of the altered (mutant) protein Huntingtin, which has a long chain of polyglutamine (poly Q) attached to the exon 1 encoded protein sequence. Clinical and statistical analyses have shown that an increased number of poly Q repetition correlates with the probability of developing the disease, with 36 to 40 being the accepted cut off number for developing the disorder with high probability. It is known that poly Q repetitions impact the physical properties of Huntingtin and cause it to produce aggregates that precipitate and form inclusion bodies, which are toxic to the neuronal cells. The compounds of this...
Summary: The NCI seeks proposals from parties interested in licensing and/or co-development for commercializing the use of TDP1 inhibitors as part of a potent and selective anti-cancer combination therapy. Description of Technology: Topoisomerase 1 (TOP1) is an essential enzyme that plays a critical role in DNA transcription and replication. TOP1 inhibitors are a known class of anti-cancer agents that work to interrupt DNA replication in cancer cells, causing cell death. Since the discovery of the TOP1 inhibitor camptothecin (CPT) from plant extracts more than 60 years ago, two CPT analogs (irinotecan and topotecan) were approved by the FDA for cancer treatment. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme involved in DNA repair created when TOP1 is inhibited. As a result, targeting TDP1 is considered a potential therapeutic approach to enhance and possibly synergize the potency of TOP1 inhibitors. While TOP1 inhibitors are...
The global market for cancer therapeutics is over $40 billion and is anticipated to continue to rise in the future. There remains a significant unmet need for therapeutics for cancers that affect blood, bone marrow, and lymph nodes and the immune system, such as leukemia, multiple myeloma, and lymphoma. The proteasome inhibitor bortezomib, which may prevent degradation of pro-apoptotic factors permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways, has been a successful mode of treatment for such cancers. However, some patient’s cancers have been found to be resistant to the drug. Researchers at the National Institutes of Health have developed novel hydrazone and diacyl hydrazine compounds that are inhibitors of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. These compounds preferentially target the proteasome assistant ATPase p97/VCP at a site...
Repurposing of androgen receptors inhibitors for prostate cancer treatment to treat other cancer in males such as melanoma. Problem: For many cancer types, women have lower incidence and better outcomes than men. The role of sex steroid hormones, such as estrogen and testosterone, has been studied in reproductive organ cancers such as prostate and breast cancer, but not in other non-androgen (AR)-driven cancers. Recent studies have shown that testosterone promotes cancer cell proliferation. Solution: Inhibiting testosterone-induced tumor growth as a new therapeutic approach for non-AR-driven cancer. Inventors: Cristina Aguirre Portolés, Christopher Natale, Todd Ridky.
First in class compounds inhibiting BRISC deubiquitinating enzymes for treatment of autoimmune diseases. Problem: Lupus is an autoimmune disease affecting approximately 5 million people worldwide. Lupus results in a hyperactive immune system and multisystem pathologic changes to joints, skin, kidneys, blood cells, and lungs. Immunosuppressive drugs are the current standard of care for lupus patients, but have unfavorable side effects and limitations leaving a need for alternative treatment methods. Solution: A majority of individuals with lupus display elevated expression of type-1 interferon (IFN) inducible genes in circulating immune cells and peripheral tissues, which correlates with disease severity. Dr. Roger Greenberg has discovered that BRISC deubiquitinating enzymes play a critical role in IFN and other inflammatory cytokine responses and showed that BRISC deficiency in mice reduces activation of immune cells and ameliorates...
Mitigating lung injury and lung inflammation through PERK pathway inhibition Problem: Acute lung injury, induced by long-term treatment with a mechanical ventilator, and acute respiratory distress syndrome (ARDS) affects 190,000 patients per year in the United States, with associated mortality of 35-40%. The highest numbers of deaths are in patients with sepsis, pneumonia, or aspiration. ARDS is characterized by sudden breathlessness within hours to days of an inciting event, including trauma, sepsis, drug overdose, blood transfusion, and aspiration. ARDS is a life-threatening condition caused by widespread inflammation of the lungs that can lead to multisystem organ failure. Currently, there is no specific therapy for acute lung injury or lung inflammation, and adjunctive strategies that modulate the deleterious effects of mechanical ventilation are needed. Solution: During lung injury, the Margulies Lab has discovered, in vitro with...
This invention relates to assays for the detection and species-specific identification of Aspergillus fungi. Accurate clinical diagnosis of Aspergillus species has become increasingly important as certain species, such as A. terreus and A. fumigatus , are resistant to specific commonly employed antifungal compounds. Most contemporary fungal diagnostic methods are time-consuming and inaccurate. This invention directly addresses those inadequacies by providing a method to rapidly and accurately differentiate all medically important species of Aspergillus based on differences in the DNA sequences of the internal transcribed spacer 1 region of ribosomal DNA. Commercial applications: Directing antifungal drug therapy for improved patient outcomes. Detection, discrimination of Aspergillus species from biological samples. Addressing secondary infections of immunosuppressed individuals or asthmatics. Competitive advantages: Easily adapted for...
This invention relates to detecting Histoplasma capsulatum by PCR using oligonucleotide probes specific for the fungus. Histoplasmosis is a mycotic infection of varying severity, usually localized in the lungs. Caused by H. capsulatum , infections are usually symptomatic but can develop into chronic disease, especially in immunocompromised individuals. Test samples may originate from the environment (soil, for example), where H. capsulatum spores are found or from clinical samples obtained from patients. Furthermore, the invention also provides for methods that detect the presence of H. capsulatum in a sample using a nested, or two-stage, PCR assay. Commercial applications: Directing antifungal drug therapy for improved patient outcomes. Occupational health and safety screening for workers who may encounter bird or bat waste. Screening biological or soil samples for the presence of fungal pathogens. Environment testing for...
The technology is directed to compositions and methods of designing nucleic acid nanoparticles (NANPs) composed entirely of DNA, RNA, or DNA and RNA to achieve desirable immunostimulation and decrease undesirable effects on the immune system by changing the composition of the NANP. Benefits of the invention include the desirable activation of the immune system by these particles to increase the efficacy of vaccines and immunotherapies. In contrast, the NANPs with minimal to no recognition by the host's immune cells serve as an effective tool for the delivery of therapeutic payloads (small molecules and therapeutic oligonucleotides) without the induction of undesirable immunostimulatory side-effects. These NANPs are highly tunable and can assume various shapes, sizes, compositions, and immunostimulatory effects; additionally, they can be designed to carry a variety of pharmaceutically active payloads simultaneously. Competitive...
RNA interference (RNAi) is a naturally occurring cellular post-transcriptional gene regulation process that utilizes small double-stranded RNAs to trigger and guide gene silencing. By introducing synthetic RNA duplexes called small-interfering RNAs (siRNAs), we can harness the RNAi machinery for therapeutic gene control and the treatment of various diseases. NCI researchers created RNA, RNA-DNA, or DNA-RNA hybrid nanocubes consisting of a DNA or RNA core (composed of six strands) with attached RNA or DNA hybrid duplexes. The nanocubes can induce the reassociation of the RNA duplexes, which can then be processed by the human recombinant DICER enzyme, thus activating RNAi. This technology opens a new route for the development of “smart” nucleic acid based nanoparticles for a wide range of biomedical applications. Immune responses can be controlled by altering the composition of the particle. The researchers are conducting preliminary...
This invention pertains to the development of oligonucleotides for the rapid nucleic acid-based identification of Candida or Aspergillus fungi species in biological samples. This identification is accomplished by the targeting the internally transcribed spacer-2 (ITS2) region that are unique to various Candida species. The assay is sensitive, specific and rapid. Implementation of the technology will facilitate earlier specific diagnoses, and lead to better antifungal therapy implementation for infected patients. Commercial applications: Directing antifungal drug therapy for improved patient outcomes. Detection, discrimination of Candida and Aspergillus species from biological samples. Addressing secondary infections of immunosuppressed individuals. Competitive advantages: Easily adapted for use in kits. High-throughput capable. Rapid and cost-effective. Source institute: CDC. Inventors: Reiss, Errol, Holloway, Brian, Shin, Jong,...
This invention pertains to the development of oligonucleotides for the rapid nucleic acid-based identification of the Candida fungi species C. haemulonii , C. kefyr , C. lambica , C. lusitaniae , C. norvegensis , C. norvegica , C. rugosa , C. utilis , C. viswanathii , C. zeylanoides , C. dubliniensis , and C. pelliculosa within biological samples. This identification is accomplished by the targeting the internally transcribed spacer-2 (ITS2) region that are specific for each species. The assay is sensitive, specific and rapid. Implementation of the technology will facilitate earlier specific diagnoses, and lead to better antifungal therapy implementation for infected patients. Commercial applications: Directing antifungal drug therapy for improved patient outcomes. Detection, discrimination of Candida species from biological samples. Addressing secondary infections of immunosuppressed individuals. Competitive advantages: Easily...
Summary: The NCI seeks research co-development partners or licensees for Nucleophosmin 1 (NPM1) Mutation-Specific T Cell Receptors for Targeted Treatment of Acute Myeloid Leukemia. Description of Technology: Acute myeloid leukemia (AML) is a rare form of blood cancer affecting myeloid stem and progenitor cells, associated with a poor prognosis and a 5-year survival rate of ~33%. Current treatments, including intensive chemotherapy and stem cell transplantation, are not suitable for all patients and can cause significant toxicities, including low blood cell counts, infection and graft-versus-host disease. Therefore, there is a need for safer and more effective treatments. This specific invention concerns the isolation of two highly specific T cell receptors (TCRs), known as TCR6 and TCR7, recognizing a neoepitope, AVEEVSLRK. The neoepitope is derived from mutant Nucleophosmin 1 (NPM1) and presented in the context of HLA-A*11:01....
This technology provides improved processes for production and purification of nucleic acid-containing compositions, such as non-naturally occurring viruses, for example, recombinant polioviruses that can be employed as oncolytic agents. Some of the improved processes relate to improved processes for producing viral DNA template. Also provided are improved processes for chromatography purification of nucleic acid-containing compositions, in which the nucleic acid is quantified in chromatography fractions using a rapid detection method of the one or more nucleic acid sequences of the nucleic acid-containing composition, such as detection by real time RT-qPCR. In addition, improved processes for production and purification of oncolytic poliovirus, such as PVSRIPO, are described. Compositions generated using these methods are also provided. Competitive Advantages: Cost and time effective means of producing highly purified virus-based GMP...
This CDC-developed technology entails a nucleic acid-based HIV-2 in vitro diagnostic assay that is well-suited for use in mobile testing units/vehicles or resource-limited settings, for example, many areas of West Africa. Because HIV-2 requires unique treatment regimens, accurate, early diagnosis is crucial for effective care and directing treatment. Recently, new HIV testing recommendations have been proposed for laboratory settings, which include the use of a HIV-1/HIV-2 discriminatory assay. The use of a discriminatory assay will aid clinicians in the detection of HIV-2 infection; however, current HIV screening tests are antibody-based and frequently yield a false-negative result if a patient is tested during early infection, prior to seroconversion. In this technology, RT-LAMP (Reverse Transcription-Loop-mediated Isothermal Amplification) provides a rapid, portable, easy to perform assay that can be used for early-stage HIV...
N-Terminal protein modification using adenosine substrates and aminoacyl transferase Problem: The conjugation of synthetic molecules to the termini of proteins with minimal effects on protein folding and function is an active area of biochemical research. Previous N-terminal protein modification methods suffer from side reaction products, incomplete specificity, low yields, and harsh organic solvent conditions. Solution: Researchers in the Petersson Lab have developed a minimal system for N-terminal protein labeling that uses an adenosine substrate of natural or unnatural amino acids and a single, readily available enzyme, aminoacyl tRNA transferase (AaT) from E. coli. The use of aminoacyl adenosyl donors increases the substrate scope and reaction scale for N-terminal protein modification. This process gives high yields of modified proteins under nondenaturing conditions to maintain natural protein folding and activity, while...
Clinical and biological specimens often contain microbial nucleic acid in extremely low quantities, presenting a significant challenge for the detection of viral and bacterial pathogens. This also prevents direct sequencing of non-culturable samples using next-generation sequencing (NGS). Currently, NGS library preparation on most platforms requires 0.1 ng to 10 µg of DNA or cDNA, while microbial or viral nucleic acids in clinically relevant specimens, such as blood, serum, respiratory secretions, cerebral spinal fluid, and stool, often contain less than 0.1 ng. CDC developed a rapid random amplification method capable of amplifying DNA and/or RNA inputs of less than 0.001 ng from biological samples. CDC’s method produces amplicons in amounts sufficient for NGS platforms. It allows non-biased universal amplification of all nucleic acids in a sample. Compared to traditional specific PCR (polymerase chain reaction), this technology...
Fluorescent ratiometric bimolecular beacons with spatiotemporal resolution Problem: Common gene expression analysis methods, including polymerase chain reaction, microarrays, and in situ hybridization rely on fixed or lysed cells, hindering their ability to provide spatiotemporal information. This led to the development of optical probes that enable the imaging of RNA in living cells, but most suffer from high levels of false-positive signals, due to non-specific interactions, nuclease-mediated degradation, and sequestration into the nucleus. Solution: Scientists in the Tsourkas Lab have designed a nucleic acid-based optical probe that, upon RNA hybridization, is capable of accurately detecting nucleic acids in living cells with high signal-to-background and little to no false-positive signals. Moreover, this ratiometric bimolecular beacon (RBMB) simultaneously measures endogenous mRNA and the efficiency of probe entry, removing...
Small MoleculeDiagnostic / BiomarkerCell/Gene Therapy
Description of Technology: Patients with chemotherapy-refractory, diffuse large B-cell lymphoma (DLBCL) have poor prognoses. CD19 and CD20 are promising targets for the treatment of B-Cell malignancies. However, despite the initial promising results from anti-CD19 CAR therapy, only 30-35% of patients with DLBCL achieve remissions lasting longer than 2-3 years after anti-CD19 CAR T-cell therapy. Relapse and non-response are likely due to diminished CD19 expression after anti-CD19 therapy and low expression of CD19 in some lymphomas. To overcome the limitations of the CD19 CAR T therapy, inventors developed an improved CAR targeting both CD19 and CD20. CARs targeting both CD19 and CD20 showed greater efficacy than the CD19 targeting CAR by itself. The structure of the CD20 binder in some of these CAR constructs is optimized to reduce death of CAR-expressing T cells and to promote retention of CAR expression. Also, these constructs are...
In this technology, researchers have engineered a modified version of Respiratory Syncytial Virus (RSV) strain A2 using reverse genetics to incorporate green fluorescent protein (GFP) into the first-gene position. This genetic modification allows for the efficient monitoring of RSV infection and the screening of potential chemical inhibitors. The GFP expression can be easily detected through fluorescence microscopy in live or fixed cells, providing a sensitive tool for both research and drug discovery. Importantly, placing GFP in the first-gene position minimizes interference with the expression of key RSV interferon antagonist genes, maintaining the virus's functionality while enhancing the brightness and utility of the GFP marker. This technology offers valuable insights into RSV infection dynamics and facilitates high-throughput screening for potential therapeutic agents. Commercial applications: This technology has versatile...
InflammationInfectious DiseaseBiologicSmall MoleculeDiagnostic / BiomarkerAI / ML
This technology discloses the use of small-molecule iron chelators—drugs that bind and remove excess iron—for the oral treatment of developmental stuttering in children and adults. Mouse models carrying human stuttering mutations show both elevated striatal iron and impaired vocalization; daily low-dose deferiprone reverses these speech-like deficits while normalizing brain-iron MRI signals. Because exemplary chelators deferiprone, deferasirox, and deferoxamine are already marketed for other indications, their safety, dosing, and manufacturing are well characterized, enabling a streamlined regulatory path. The approach offers the first disease-targeted pharmacologic option for a disorder currently managed only by speech therapy. Commercial applications: Stand-alone or adjunctive pharmacotherapy for persistent developmental stuttering in pediatric and adult populations.. MRI-guided precision treatment platform for speech-motor...
This invention portrays a simple method for treatment of antigen-deficiency diseases by orally administering to a subject a therapeutically effective amount of the deficient antigen, wherein the antigen is not present in a liposome. This method increases hemostasis in a subject having hemophilia A or B, by orally administering to the hemophiliac a therapeutically effective amount of the appropriate clotting factor, sufficient to induce oral tolerance and supply exogenous clotting factor to the subject. Commercial applications: Oral-based treatment for hemophilia A or B. Competitive advantages: Less invasive than current modes of treatment. Reduced inflammatory response. Immunotolerization against future bleeding episodes. Source institute: NIAID. Inventors: Alpan, Oral, Matzinger, Polly, Kamala, Tirumalai, Velander, William.
Peptide-functionalized lipid nanoparticles (pLNPs) for targeted messenger RNA (mRNA) delivery to the brain. Problem: Ionizable lipid nanoparticles (LNPs) have emerged as clinically advanced delivery vehicles for nucleic acids. However, as LNPs typically accumulate to the liver, tissue-specific delivery remains challenging, and systemic LNP delivery to the brain is particularly challenging due to the highly selective blood-brain barrier (BBB). Current targeting approaches mainly use antibodies or proteins that bind to receptors overexpressed on the BBB. Although these ligands have high affinity to the BBB, they often have high immunogenicity, are large, expensive, and susceptible to degradation. Thus, alternative strategies are needed for LNPs to successfully cross the BBB and deliver nucleic acid therapeutics to the brain. Solution: LNPs are functionalized with brain-targeting peptides, which are much smaller alternatives to...
T cell-based immunotherapy (such as CAR therapies) is a promising approach for the treatment of several cancers. However, T cells currently employed for various T cell-based immunotherapies are usually senescent and terminally differentiated leading to poor proliferative and survival capacity, limiting their therapeutic effectiveness once transferred into a patient’s blood. Researchers in the National Cancer Institute (NCI) Experimental Transplantation and Immunology Branch (ETIB) have epigenetically reprogrammed CD8+ T cell fate by overexpressing Phf19. The inventors found that overexpression of Phf19 in tumor-reactive CD8+ T cells limits T cell terminal differentiation and exhaustion. In addition, it was found that Phf19 overexpressing T cells exhibit enhanced proliferation and cytokine production, resulting in augmented anti-tumor activity in vivo. This technology is available for licensing and/or co-development. Competitive...
Summary: The National Cancer Institute (NCI) is actively seeking potential licensees and/or co-development research collaboration partners interested in advancing oxynitidine derivatives as novel inhibitors of topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) for cancer treatment. These TOPI and TDP1 inhibitors, when administered together, demonstrate enhanced anti-tumor efficacy. Description of Technology: Topoisomerase 1B (TOP1) is an enzyme that relieves DNA torsional strain through the formation of transient TOP1-DNA covalent cleavage complexes (TOP1ccs) and is an attractive target for anti-cancer therapeutics. TOP1 inhibitors – such as camptothecin (CPT) – stabilize TOP1ccs, which ultimately leads to cell death. TOP1 inhibitors have long been recognized as anti-cancer agents and are used clinically. However, existing TOP1 inhibitor CPT, is limited by toxicity, chemical instability, poor solubility, and potential...
Summary: The National Cancer Institute (NCI) is actively seeking potential licensees and/or co-development research collaboration partners interested in further developing this family of oxynitidine derivatives as tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors and radiosensitizers for the treatment of cancer. Description of Technology: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that promotes the repair of DNA damage caused by common anti-cancer interventions, such as ionizing radiation (IR) and topoisomerase 1 (TOP1) chemotherapy. This enzyme plays a critical role in repairing the trapped DNA cleavage complexes induced by clinically used TOP1 chemotherapy (such as irinotecan and topotecan). TDP1 also plays a regulatory role in non-homologous end joining (NHEJ) in the repair of DNA double-strand breaks and damage caused by ionizing radiation. In both cases, this leads to a diminished therapeutic effect of the intervention...
This technology includes the development of selective P2Y14R antagonists for the treatment of asthma, sterile inflammation of the kidney, diabetes, and neurodegeneration. The P2Y14 receptor (P2Y14R) is a target for the treatment of inflammatory diseases, including pulmonary and renal conditions. Selective P2Y14R antagonists have demonstrated efficacy in animal models of asthma, pain, diabetes, and acute kidney injury. However, the prototypical antagonist is not optimal for in vivo administration, as it displays a low oral bioavailability. This invention includes P2Y14R antagonists that contain sterically constrained, bridged piperidine modifications or uncharged bioisosteres of the piperidine moiety. This approach aligns with a general trend to improve druglikeness in medicinal chemistry by adding three-dimensionality to otherwise flat molecules. We also invented prodrugs of the most potent analogs that display significant in vivo...
Poly-ADP ribose polymerase-1 (PARP-1) is a critical enzyme involved in DNA repair. The inhibition of PARP has emerged as a promising strategy in cancer therapy. Numerous PARP inhibitors have been developed and advanced into clinical trials, both for use as single agents in specific patient populations and as combination therapies with various chemotherapeutics. The induction of strand break damage to DNA, as has been demonstrated in cancer cells treated with O2-arylated diazeniumdiolates, coupled with inhibition of DNA repair by PARP inhibitors, represents a novel rationale for effective combination therapy. Scientists at NCI developed prodrugs that combine structural features of the known PARP inhibitor olaparib with an O2-arylated diazeniumdiolate in one hybrid molecule. The two-component prodrug has the advantage of delivering both a DNA damaging agent (NO) and an inhibitor of DNA repair (PARP inhibitor) simultaneously to a cancer...
Description of Technology: Proviral Integration for the Moloney murine leukemia virus (PIM) kinases are overexpressed in many solid cancers – including prostate, breast, colon, endometrial, gastric and pancreatic. High of PIM1 expression is predictive of poor survival in multiple cancer types. While several selective pan-PIM inhibitors were developed and tested in clinical trials, all ultimately increased PIM1-3 protein levels and developed intrinsic resistance. Researchers at the National Institutes of Health (NIH) developed multiple PIM kinase-targeting proteolysis-targeting chimeras (PROTACs) that lead to PIM1 degradation in a prostate cancer cell model and increased chemo-sensitization. The targeting of PIM kinases for degradation provides superior catalytic inhibition as these compounds target pro-tumorigenic functions of the PIM kinases, which are not linked to kinase activity. Additionally, these PROTACs prevent the onset of...
Available for licensing and commercial development are compositions and methods for the treatment and inhibition of Methicillin-resistant Staphylococcus aureus (MRSA), a dangerous human pathogen. The invention concerns immunogenic peptides that can be used to induce protective immunity against MRSA, including phenol-soluble modulin (PSM) peptides. In addition to the MRSA infections that occur in immunocompromised patients in hospitals, new MRSA strains have recently emerged that can cause severe infections (such as necrotizing fasciitis) or death in otherwise healthy adults. These strains are increasingly involved in community-associated (CA)-MRSA infections, and can be contracted outside of the health care settings. The incidence of CA-MRSA infections is increasing and the majority of infections in patients reporting to emergency departments in the US is now due to CA-MRSA. The invention describes a class of secreted staphylococcal...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for a hydrogel-based delivery system for the local administration of tofacitinib to improve transplant outcomes. Description of Technology: More than 1 million tissue transplantations are performed each year. Organ transplantation therapies are typically combined with immunosuppressive agents to reduce the risk of allograft rejection and enhance transplant survival. Currently, immunosuppressive drugs are administered systemically and have several dose-limiting side effects, including impairment of renal function, hypertension, and lymphatic malignancies. Therefore, there is an unmet need to identify a safer, more effective treatment plan for transplant recipients. A multidisciplinary team of researchers from the National Cancer Institute (NCI) and Johns Hopkins University (JHU) developed a peptide hydrogel containing a crystalized form...
Description of Technology: Hydrogels represent an attractive controlled drug-delivery system that have been used in various clinical applications, such as: tissue engineering for wound healing, surgical procedures, pain management, cardiology, and oncology. High-water content of hydrogels confers tissue-like physical properties and the crosslinked fibrillar network enables encapsulation of labile small molecule drugs, peptides, proteins, nucleic acids, proteins, nanoparticles, or cells. The porosity of the mesh-like network contributes to enhanced protection and controlled release of therapeutics compared with the rapid clearance and degradation of some proteins observed using conventional drug-delivery methods. Although all hydrogel platforms provide spatial and temporal control over the release of therapeutics, the current standard requires designing a unique hydrogel for a select therapeutic agent for a specific application. This...
IFN-gamma and IL-10 are cytokine signaling molecules that play fundamental roles in inflammation, cancer growth and autoimmune diseases. Unfortunately, there are no specific inhibitors of IFN-gamma or IL-10 on the market to date. NCI investigators at the Cancer and Inflammation Program have synthesized short peptides that selectively interfere with dimerization of the cytokines and their binding to the corresponding receptor. The peptides include metabolically stable lipopeptides mimicking conserved regions of IL-10 and IFN-gamma receptors that interfere with STAT3 and STAT1 phosphorylation and subsequent signaling. The lipopeptides strongly inhibit STAT3 and STAT1-dependent growth of cancer cells. These compounds are promising drug candidates for the treatment of cancer and many infectious and inflammatory diseases. Competitive Advantages: - Rationally designed and synthesized to be potent, metabolically stable, and more therapeutic...
The invention includes compounds and compositions for inhibiting phosphoglycerate mutase (PGM) activity. In some examples, the compounds selectively inhibit cofactor-independent PGM (iPGM). In particular embodiments, the compounds include one or more cyclic peptides. The co-factor independent phosphoglycerate mutase (iPGM) is an essential glycolytic enzyme and validated target in several infectious organisms structurally distinct from its human isozyme. iPGM, present in several types of parasitic roundworms, including Brugia malayi and Onchocerca volvulus, infects roughly 150 million people living mostly in tropical regions. The parasites can cause devastating infectious diseases, such as river blindness. The enzyme also is found in bacteria, including Staphylococcus aureus, which can cause the hospital-borne infection MRSA (methicillin-resistant Staphylococcus aureus), and anthrax. However, the enzyme has been considered...
Polo-like kinase 1 (Plk1) is a critical protein involved in regulation of mitosis, and aberrant expression of this kinase is found in various cancer types. Inhibition of Plk1 is currently being pursued in pre-clinical drug development for novel anti-cancer therapeutics. Plk1 contains an allosteric domain, known as the polo-box domain (PBD), that is responsible for localizing the kinase domain to mitotic structures through protein-protein interactions. This technology is an improvement and continuation of Dr. Terry Burke’s research program centered around PBD modulation. The “Plk1 PBD” portfolio focuses on compounds that disrupt Plk1-mediated protein interactions. These compounds are designed to selectively cause mitotic arrest in cancer cells with abnormal Plk1 expression by inhibiting proper localization of Plk1. The invention is directed to improved design and synthesis of peptidomimetic ligands that bind PBD by attaching a...
Polo-like kinase 1 (Plk1) is a critical protein involved in regulation of mitosis, and aberrant expression of this kinase is found in various cancer types. Inhibition of Plk1 is currently being pursued in pre-clinical drug development for novel anti-cancer therapeutics. Plk1 contains an allosteric domain, known as the polo-box domain (PBD), that is responsible for localizing the kinase domain to mitotic structures through protein-protein interactions. The invention is directed to improved peptidomimetic inhibitors that disrupt Plk1-mediated protein interactions by targeting PBD. These compounds are designed to selectively cause mitotic arrest in cancer cells with abnormal Plk1 expression by inhibiting proper localization of Plk1. In doing so, such ligands could avoid issues of off-target activity and dose-limiting toxicities that are characteristic of some ATP-competitive kinase inhibitors. This invention is an improvement and...
CDC researchers have isolated select Chlamydophila pneumoniae peptide epitopes for development of vaccines and diagnostic assays. Currently, C. pneumoniae infection of humans has been linked to a wide variety of acute and chronic diseases, such as asthma, endocarditis, atherosclerotic vascular disease, chronic obstructive pulmonary disease, sarcoidosis, reactive arthritis and multiple sclerosis. There is presently no available peptide vaccine for the pathogen and reliable and accurate diagnostic methods are limited. This technology encompasses polypeptide sequences that are specifically recognized by anti- C. pneumoniae antibodies. These antigens may be useful for improving diagnostic methods by reducing the variability and high backgrounds found with methods that rely on whole organisms for detection. Further, this technology may also be useful for production of peptide or DNA-based vaccines directed against C. pneumoniae ....
This invention relates to synthetic immunoreactive peptides, which are portions of the M proteins of the most prevalent Group A Streptococcus (GAS) serotypes in the United States. These peptides may be useful in development of a flexible, multivalent GAS vaccine. They can be recognized by M type-specific antibodies and are capable of eliciting functional opsonic antibodies. Additionally, the peptides or isolated antibodies raised in response to the peptides may be useful for GAS diagnostics. Commercial applications: Group A streptococci (GAS) vaccine. GAS therapeutics and diagnostics. Lab tools for exploring GAS. Competitive advantages: Easily adaptable to kit form. Multivalent vaccine that can be tailored for protection against specific GAS serotypes affecting a particular population. Source institute: CDC. Inventors: Carlone, George, Sampson, Jacquelyn, Ades, Edwin, Beall, Bernard.
Short, multivalent peptide antagonists to block macrophage immune-receptor SIRPα, promoting cancer cell phagocytosis. Problem: Modern cancer cell immunotherapies incorporate immune checkpoint blockade mechanisms, where prominent therapies target functionally suppressed immune cells in tumor microenvironments. Relieving this suppression allows immune cell simulation, eliminating targets of cancer. Current strategies for immune checkpoint blockades focus on T cells, which can be stimulated through immunotherapy to destroy cancer cells. This treatment is ineffective on solid tumors, as T cells cannot infiltrate into solid tumors. Additionally, indiscriminate immune checkpoint blockading of healthy cells such as blood cells can lead to toxic side effects, such as anemia. Solution: A macrophage-based treatment which can infiltrate into solid tumors, allowing for the treatment of both liquid- and solid-state tumors. This treatment targets a...
Tumor Necrosis Factor alpha (TNF-alpha) is a multifunctional cytokine that mediates inflammation, immune regulation, and cellular proliferation. This cytokine is converted to its active form by TNF-alpha converting enzyme (TACE). Pathological increases in TNF-alpha activity have been associated with a wide variety of inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, and cancer. Inhibiting the conversion of TNF-alpha to its active form by inhibiting TACE represents a potential treatment for these diseases. The current technology provides peptides, derived from an N-terminal fragment of the TACE protein, that inhibit TACE activity. Also described are methods of using these peptides to lower levels of active TNF-alpha. These peptides could be used as a treatment for TNF-alpha-mediated inflammatory diseases. Commercial applications: Treatment of TNF-alpha mediated inflammatory diseases. Competitive...
This invention consists of a sampling apparatus that utilizes one or more cyclone separators to collect airborne particles from the atmosphere. The apparatus not only separates out aerosols from the atmosphere, but also serves as a collection tube for aerosol particles. Through its unique design, this CDC-developed apparatus is able to use the centrifugal force of the air flow on aerosolized particles forcing them to separate by size. Since the sample is collected directly in a microcentrifuge tube, in situ analysis of the ambient particulates can be performed. Analysis may include, but is not limited to, PCR, immunoassay analysis, microscopic spore counting, and counting colony-forming units. The device should also have many additional uses for environmental surveillance and occupational health applications. Commercial applications: Analysis of ambient air particulates. Environmental surveillance. Occupational safety monitoring....
Attempts to manage body weight are often unsuccessful or only temporary. This is, in part, due to antiquated dieting methods that attempt to address calorie consumption while ignoring metabolic and physical changes. Personalized and more comprehensive methods to track and manage body weight may be more effective. To that end, scientists at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) developed and launched the Body Weight Planner ( http://www.niddk.nih.gov/health-information/weight-management/body-weight-planner ) that uses validated mathematical models of human metabolism to set weight management goals and predict individual body weight outcomes in the context of changing metabolic needs and calorie consumption. More recently, developers at NIDDK have created a prototype personalized body weight management system that builds on the science behind Body Weight Planner with the addition of patented...
A novel and innovative organoid co-culture system for studying immune-mediated tissue damage and testing patient responses to therapies for inflammatory disorders.
Pervious polymersomes encapsulate antioxidant agents while allowing reactive oxygen species to enter through diblock copolymer-defined channels. Problem: Reactive oxygen species and oxidative stress are associated with osteoarthritis development and myocardial injury. Direct use of antioxidant enzymes is challenging due to insufficient delivery systems. Enzyme payloads may require protection and retention while remaining accessible to reactive oxygen species. These limitations create a need for delivery systems that support antioxidant enzyme treatment. Solution: Dr. Zhiliang Cheng and his team developed a technology that uses a pervious polymersome that encapsulates an anti-reactive oxygen species agent. Channels formed by a channel diblock copolymer allow reactive oxygen species to pass into the polymersome. The channels are arranged to retain at least some of the agent within the polymersome. The technology supports therapeutic...
The inventors have isolated and characterized an alkaloid, phantasmidine, from the skin of the Ecuadoran poison frog E. anthonyi . Phantasmidine is selective for beta4-containing receptor subtypes, unlike many nicotinic receptor agonists currently in development, which target beta2-containing receptor subtypes. This selectivity makes phantasmidine a unique pharmacological probe, as well as a promising lead compound for the development of selective therapeutics targeting beta4-containing receptor subtypes, which appear to play any important role in nicotine addiction and other substance dependencies. Nicotinic acetylcholine receptors (nAChRs) are broadly distributed in both the peripheral and central nervous systems; activation of brain nAChRs results in enhanced release of various key neurotransmitters. Dysfunction of these receptors is associated with a variety of neurological diseases, including nicotine addiction. Nicotinic...
Histone deacetylase (HDAC) inhibitors such as Trichostatin A to treat bronchoconstrictive diseases including asthma and chronic obstructive pulmonary disorder (COPD) Applications: Small molecule therapeutic that dilates bronchi to treat asthma and other lung diseases Inventors: Jonathan Epstein, Reynold Panettieri.
Targeting Heat Shock Factor 1 (HSF1) via gene therapy or using pharmacological compounds targeting HSF1 (e.g. geranylgeranylacetone or macrocyclic peptides) can increase sleep stability, promote deeper sleep, reduce sleep fragmentation, and improve recovery from sleep loss. Problem: Millions of people worldwide suffer from disrupted sleep, whether due to modern "24/7" lifestyles, stress, aging and menopause, or underlying health conditions. Yet current treatments largely sedate patients without actually improving the quality of sleep - they can disrupt normal sleep architecture and fail to promote the deep, restorative stages that the brain and body need. This matters because poor sleep is not merely an inconvenience but is closely linked to cognitive decline, neurodegenerative disease, and reduced productivity. There is thus a critical need for therapies that restore how sleep naturally works, rather than simply masking symptoms....
Bitter taste has evolved in mammals as a central warning signal against ingestion of poisonous or toxic compounds. However, many beneficial compounds are also bitter and taste masking of bitter tasting pharmaceutical compounds is a billion dollar industry. The diversity of compounds that elicit bitter-taste sensations is vast and more than two dozen members of the TAS2R bitter taste receptor gene family have been identified. How individuals are genetically predisposed to respond or not to respond to the bitter taste of substances like nicotine and certain foods like broccoli may have broad implications for nutritional status and tobacco use. Large individual differences in the taste perception of bitter compounds have been well documented, and phenylthiocarbamide (PTC), the subject of this invention by scientists at the NIH and the University of Utah, has been widely used for genetic and anthropological studies. The PTC receptor...
Problem: Phorboxazoles are naturally occurring compounds that have been isolated from the marine sponge Phorbas, endemic to the western coast of Australia. Previous screens of phorboxazoles against the National Cancer Institute human cell line panel indicated the most potent cytotoxicity assayed. While the mechanism of action in vivo is unknown,... Problem: Phorboxazoles are naturally occurring compounds that have been isolated from the marine sponge Phorbas, endemic to the western coast of Australia. Previous screens of phorboxazoles against the National Cancer Institute human cell line panel indicated the most potent cytotoxicity assayed. While the mechanism of action in vivo is unknown, phorboxazole arrests the cell cycle at S phase without interfering with microtubule stability. Because of the antimitotic bioactivity, structural complexity, and extreme natural scarcity of the compound, efforts have been underway for the total...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for a new series of photo-absorbing silicon-phthalocyanine derivatives (IR702HKT) for use in near-infrared photoimmunotherapy (NIR-PIT) in the treatment of cancer. Description of Technology: Near-infrared photoimmunotherapy (NIR-PIT) is a method of treating cancers that utilizes an antibody-photoabsorber conjugate (APC), which is activated by near-infrared light to kill cells. The antibody binds to the appropriate cell surface antigen and a photo-activatable compound induces lethal damage to the cell membrane after NIR-light exposure. NIR-light exposure induces highly selective, necrotic cancer cell death within minutes without damage to adjoining cells. Researchers at the National Cancer Institute (NCI) and Kansai Medical University (KMU) have developed the current invention which is a new series of photo-absorbing...
The invention relates to novel lipid-based nanoparticles (liposomes) for use in targeted, on demand and on site drug delivery. The particles include a wall surrounding a cavity, wherein the wall is comprised of: A lipid bilayer comprising 1,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC 8,9 PC), dipalmitoylphosphatidylcholine (DPPC), and 1,2-distearoyl- sn -glycero-3-. phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000), and A tetrapyrollic photosensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) within the lipid bilayer.. The photosensitive lipid nanoparticles are capable of containing water-soluble agents (e.g., topotecan) in their cavity and designed to be 80-200nm in diameter. The release of agents is triggered by the disruption of the lipid bilayer when light (near-infrared wavelength of 650-670nm) is discretely applied. The concurrent activation of the photosensitizing agent,...
CDC scientists have developed a rapid and cost-efficient method for generating fluorescently labeled primers for PCR and real-time PCR. At present, fluorescent primers are useful for detecting and identifying microbes and specific nucleic acid sequences, amplifying nucleic acids for pyro-sequencing, determining the levels of gene expression, and many other uses. However, problems exist with current techniques used to create fluorescent primers. For one, labeling is not one hundred percent efficient, leading to inaccurate results. Further, it is expensive and time consuming for researchers to make and label their own unique primers. This technology allows for the creation of custom primers in which fluorescent dye attaches to all oligomers. This technology employs photoinduced electron transfer (PET) nucleic acid molecules that can be used detect and amplify target nucleic acid molecules. PET tags are attached to the 5'-end of a...
NeurologyOphthalmologyOncologyInfectious DiseaseImmunologyCardiometabolicInflammationBiologicDiagnostic / BiomarkerAI / ML
This CDC developed physiologic sampling pump (PSP) overcomes shortcomings of previous devices by the use of calibrated valves in conjunction with a constant speed pump. This novel approach obviates typical PSP inertia that inherently limits system response, functionality and accuracy. All prior PSP designs have attempted to follow a user's breathing pattern by changing pump speed, thereby altering sampling rate. In that approach, pump inertia will limit system response and function due to the time required to adjust speed. Additionally, variable pump speeds often produce size selective sampling errors at low flow rates. Performance of this PSP is not degraded by pump inertia or low flow size selective sampling errors. This design maintains a consistent pump speed, controlling PSP sampling rate with calibrated valves that redirect air flow almost instantaneously. In situ device testing demonstrated that when this air-flow valve is...
Summary: The National Eye Institute (NEI) seeks research co-development partners and/or licensees for the development of an AAV2-based delivery system or an eyedrop formulation to deliver a Pigment Epithelium-Derived Factor (PEDF) peptide as a gene-agnostic approach to treating inherited retinal diseases. Description of Technology: Retinitis pigmentosa (RP) is one of the most common inherited retinal diseases (IRDs) – estimated to affect 1 in 4,000 people worldwide. Over 100,000 people in the US and 1.5 million people worldwide suffer from RP. This disease leads to progressive photoreceptor cell degeneration and, ultimately, vision loss. More than 90 genes are implicated in molecular pathways towards photoreceptor cell death. Due to this high heterogeneity, therapeutic approaches targeting specific genes generally benefit few patients. For most forms of RP, few or no medical options are available. Thus, there remains a need to...
The technology includes Pink1 knockout HeLa cells that were generated using CRISPR technology. Pink1 is the key master gene to trigger degradation of mitochondria, mitophagy, and is implicated in familial Parkinson Disease. Knocking out Pink1 allows us to study the roles of Pink1 in many aspects of mitophagy and to display Pink1-dependent or independent activity. To create the HeLa cells, two CRISPR gRNAs targeting exon 1 and exon 7 of the Pink1 genome were used for transfection with Cas9 and GFP-C1 reporter. Cells were sorted 2 days after transfection and plated out in 96-well plates. Ten days later, single colonies were transferred to 24-well plates and then genomic DNA of each colony was isolated for genotyping. The positive clones were then confirmed by Western blot. Commercial applications: The knockout cells permit studying different regulation events related to Pink1 (such as phosphorylation or kinase mutants). The knockout...
Drug delivery technologies have long claimed the ability to selectively deliver therapeutic cargo to target cells. Despite advances in nanomedicine and drug delivery systems, there are no targeted nanoscale drug delivery technologies on the market. Thus, there is still tremendous potential in improved therapeutic efficacy when targeted drug delivery is achieved. Investigators at the Nanotechnology Characterization Laboratory at the National Cancer Institute (NCI) developed a drug delivery platform that targets scavenger receptor A1 (SR-A1), a receptor highly expressed in macrophages, monocytes, mast cells, dendritic cells (myeloid lineages), and endothelial cells. The platform is based on the anionic polymer poly (L-lysine succinylated), which contains side chains with pendant carboxylic acids that allow conjugation of small molecule drugs through hydrolysable ester bonds and have demonstrated drug release half-lives greater than 10...
CDC researchers have developed a potent immunogenic enhancer polypeptide useful for improving flavivirus vaccines. Flaviviruses such as dengue virus (1, 2, 3 and 4), Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, yellow fever virus and tick-borne encephalitis virus are a great burden on public health. This technology describes an identified CD4+ T cell epitope occurring within the E-glycoprotein of West Nile virus and methods of using this polypeptide to increase vaccine immunogenicity in monovalent vaccines. Many attempts to develop multivalent flavivirus vaccines have encountered difficulties due to widely variable immunogenicity between serotypes and related interference issues. This technology will be useful for stabilizing and enhancing efficacy by increasing immunogenicity of the weaker components of the vaccine, creating a more balanced vaccine. Additionally, in vivo murine studies...
HMGN polypeptides belong to the high mobility group (HMG) family of chromosomal binding peptides. HMGN polypeptides typically function inside the cell nucleus to bind to DNA and nucleosomes and regulate the transcription of various genes. HMGN polypeptides also can be released by peripheral blood mononuclear cells. However, the extracellular release of a HMGN polypeptide initiates activation of the immune system. Therefore, it has potential use as a biological therapeutic for stimulating an immune response. Therefore, HMGN has potential use as a clinically effective immunoadjuvant for use in vaccines against tumors and many intracellular pathogens. Researchers at the National Cancer Institute, Laboratory of Cancer Immunometabolism developed compositions and methods for using HMGN and its derivatives as immunoadjuvants with microbial or tumor antigens. HMGN can be fused to an antigen gene to produce recombinant fusion proteins or can...
Many individuals with ongoing and severe dental problems are faced with the prospect of permanent tooth loss. Examples of such dental problems include: dentinal degradation due to chronic dental disease (caries or periodontal); mouth injury; or through surgical removal, such as with tumors associated with the jaw. For many, a technology that offers a possible alternative to artificial dentures by designing and transplanting a set of living teeth fashioned from an individual's own pulp cells would greatly improve their quality of life. The NIH announces a new technology wherein human postnatal deciduous dental pulp stem cells commonly known as "baby teeth", are used to create dentin and have been shown to differentiate into cells of specialized function such as neural cells, adipocytes, and odontoblasts. It is believed that these cells could be manipulated to repair damaged teeth, induce the regeneration of bone, and treat neural...
Adoptive cell therapy (ACT) using tumor-specific T cells can produce positive clinical responses in some cancer patients. Nevertheless, several obstacles to the successful use of ACT for the treatment of cancer and other conditions remain. For example, one or more of the in vivo persistence, survival, and antitumor activity of tumor-specific T cells can, in some cases, decrease following adoptive transfer. Accordingly, there is a need for methods of obtaining a robust population of tumor-specific T cells for ACT. Researchers at the National Cancer Institute (NCI) have discovered a novel method to generate long-lived memory tumor-specific T cells with enhanced anti-tumor activity for ACT using potassium hydroxy citrate. Tumor-specific murine T cells grown ex vivo in potassium hydroxy citrate demonstrate enhanced tumor clearance and persistence upon transfer to tumor-bearing mice. Mechanistically, potassium hydroxy citrate treatment...
Monoclonal antibodies (mAbs) have become a mainstay of therapy for many cancers. However, antibody therapy is not completely effective in some applications due to loss of the target surface antigen on cancer cells. Such mAb-induced “escape variants” are no longer sensitive to the therapeutic mAb therapy. It was observed that the escape variants carried covalently bound complement activation fragments, especially C3d. NIH inventors have generated several C3d-specific mouse and rabbit monoclonal antibodies to re-target cells that have escaped from mAb therapy. Proof of principle for this “one-two punch” approach in preclinical models indicates that these C3d specific antibodies can potentiate the anti-tumor activity of therapeutic mAbs and eliminate antigen loss variants that survive after antibody therapy. This approach can enhance mAb-dependent cancer cells killing in an additive or even synergistic way, and will play a prominent role...
The technology described involves the use of a compound called prazole as an anti-viral agent specifically targeting HIV-1. It was found that prazole binds to a protein called Tsg101, which is crucial for the virus's life cycle. This binding disrupts the normal interaction of Tsg101 with another protein, ubiquitin, thereby inhibiting the release of HIV-1 particles from infected cells. Additionally, the interference caused by prazole leads to the degradation of the viral protein Gag within host cells. Remarkably, any viral particles that do manage to get released in the presence of the drug are rendered non-infectious, further highlighting the potential of prazole as an effective anti-HIV agent. Commercial applications: This technology has potential applications in developing new antiretroviral therapies for HIV, offering a promising avenue for both treatment and reduction of viral transmission. Competitive advantages: The competitive...
Using tiny lipid nanoparticles (LNPs) to improve mRNA medicine delivery and uptake in the placenta for healthier pregnancies Problem: The placenta is an important biological barrier that connects the mother and fetus while keeping their blood supplies separate, enabling nutrient and oxygen delivery and waste removal for healthy development. Abnormal development, such as in pre-eclampsia, can create serious health risks for both mother and baby during pregnancy. With no current existing cure, researchers are exploring lipid nanoparticles (LNPs) to deliver mRNA as a potential therapy. However, organ-specific LNP delivery requires modifying LNP properties like size, charge, stiffness, and stability, which influence efficacy and uptake. For treating developmental disorders like pre-eclampsia, there is a need for engineering LNP design for targeted delivery to placental cells. Solution: The authors developed a set of LNPs with varying...
Investigators at the NIH have discovered a potential means for preventing or treating a herpes virus infection by inhibiting the activity of the host cell’s histone demethylases. When herpesviruses enter a cell, they are inactivated by cellular defense mechanisms that wrap the viral genome in repressive chromatin structures. In order for viral replication to progress, the host’s own histone demethylases are recruited to the viral genome to reverse this repression. In a preceding invention, the laboratory disclosed that viral replication and reactivation can be significantly reduced through inhibition of the histone demethylase LSD1 using Mono-Amino Oxidase Inhibitors (MAOIs); drugs that are in clinical use. The current invention further discloses that inhibition of a second set of histone demethylases (JMJD2 family) using a specific JMJD2 inhibitor, dimethyloxaloylglycine (DMOG), also results in significant repression of herpes viral...
Herpes simplex viral infections, including herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), are exceptionally common worldwide. These viruses establish lifelong persistent infections with cycles of lytic reactivation to produce recurrent diseases including oral and genital lesions, herpetic keratitis/blindness, congenital-developmental syndromes, and viral encephalitis. Infection with HSV-2 increases the rate of human immunodeficiency virus (HIV) transmission in coinfected individuals. DNA replication inhibitors are typically used to treat herpesvirus infections. However, these compounds do not completely suppress infection, viral shedding, reactivation from latency, and the inflammation that contributes to diseases such as keratitis. An unmet need continues to exist for methods of preventing or treating herpesviral infections. The application claims methods of preventing or treating herpesviral infection of a host, comprising...
Prodrug lipid nanoparticle (LNP) with a mRNA encoding for a therapeutic cytokine for solid tumor immunotherapy. Problem: Approximately 2 million people are diagnosed with cancer each year in the United States. Messenger RNA (mRNA)-based cancer immunotherapy has emerged as a potential cancer treatment using cytotoxic T cells to eliminate... Problem: Approximately 2 million people are diagnosed with cancer each year in the United States. Messenger RNA (mRNA)-based cancer immunotherapy has emerged as a potential cancer treatment using cytotoxic T cells to eliminate cancer cells. However, this treatment is associated with T cell exhaustion, which limits the effectiveness of immunotherapy. Recently, mRNA-based cancer therapies have been combined with immune checkpoint blockade therapies to inhibit T cell exhaustion, but this has only been successful in a limited number of patients due to treatment resistance and low response rates. These...
Adeno-associated virus (AAV) is being developed for gene therapy applications. This virus type presents several advantages over alternate vectors for therapeutic gene delivery. AAV is not considered pathogenic and transduces stably dividing and non-dividing cells. AAV also shows good serotype specificity to various cell types for targeted gene delivery. The present invention describes a highly scalable adeno-associated virus (AAV) vector production method in insect cells. The system for producing recombinant AAV (rAAV) uses the AAV Rep protein and an AAV ITR. This production method produces virus particles much more efficiently than the standard mammalian cell culture system. Yields of rAAV produced in Sf9 cells exceed 10e15 per liter for some constructs. The improvement in production efficiency translates into lower production costs and potential for commercial scale manufacturing. In addition, all serotypes of AAV can be produced,...
A lung-targeted, resistance-proof prophylactic that prevents inflammatory lung injury from respiratory viral infections without systemic immunosuppression and pathogen clearance.
Use of functional recombinant ACE2 and Angiotensin-(1-7) proteins to improve the clinical course of patients with symptomatic COVID-19 infection. Problem: COVID-19 is associated with high rates of respiratory failure, cardiac injury and death. Patients suffering from COVID-19 generally present with reduced expression of angiotensin converting enzyme 2 (ACE2) and depletion of ACE2’s protein product, the anti-inflammatory peptide Angiotensin-(1-7). This down-regulation of ACE2 expression is induced by viral invasion of SARS-CoV-2, the virus causing COVID-19 disease. Decreased ACE2 expression has been linked to acute respiratory distress, severe lung injury, multi-organ failure and death, especially in older patients. Solution: As a potential treatment for the severe complications of COVID-19 disease, oral supplementation of ACE2 and Angiotensin-(1-7) are being tested in a clinical trial to determine whether this intervention elicits...
Non-naturally occurring protein sequences that enhance or suppress the activity of hormone associated with obesity and nausea Problem: Growth differentiation factor-15 (GDF15) is a broadly expressed hormone, whose level often correlates with progression of many diseases. It has been shown in multiple species that the elevated level of GDF15 drives weight loss primarily by reducing total food intake. The increased level of GDF15 is also seen after a cancer therapy that often associates with nausea and emesis. It was only in 2017 when a receptor responsible for mediating the anorectic actions of GDF15 was identified. Hence, the hormone and its receptor are promising therapeutic targets for the treatment of disorders such as obesity, anorexia, and nausea associated with chemotherapy. Nausea from chemotherapy and morning sickness is difficult to manage and can be extremely debilitating and compromise individual quality of life. Solution:...
A class of pyrazole derivatives that inhibit palmitoyl-transferases, resulting in increasing cancer cell responsiveness to epidermal growth factor receptor inhibitor and KRas mutant lung cancer growth inhibition as a single agent. Problem: Pancreatic and lung cancers are largely driven by either Epidermal growth factor receptor (EGFR) mutation KRAS mutations. However current therapies targeting either of these mutated proteins are either unavailable (KRas G12S/D/V/R) or rapidly develop resistance mutations (EGFR, KRas G12C). No targeted therapeutic options exist for mutant KRAS G12S/D/V/R tumors, making treatment of these cancers difficult and dependent on conventional chemotherapy and radiation. Solution: Pyrazole derivatives that increase sensitivity to EGFR inhibitors by creating a dependency on EGFR signaling for cancer cell survival, increasing responsiveness to EGFR inhibitor therapy. Additionally, the increase in EGFR signaling...
Innovative approach to correct C9ORF72 Loss-of-Function and restore protein levels in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
The development of RNA-based nanostructures and their use in a variety of applications, including RNA interference (RNAi) and drug delivery, represents an emerging field of science, technology, and biomedicine. RNA is a dynamic material because of its natural functionalities, its ability to fold into complex small structures, and its capacity to self-assemble. Taking advantage of these characteristic, NCI Researchers have improved upon their existing invention of multi-functional RNA/DNA nanoparticles by adding a RNA toehold instead of a DNA toehold. In in vitro studies, they have shown that the nanoparticles are capable of inhibiting HIV-1 gene expression in Hela cells transfected with a HIV-1 infectious clone and GFP expression in MDA-MB231 breast cancer cell lines transfected with eGFP. Competitive Advantages: Small size. Chemical stability. Less immunogenic. Commercial Applications: Therapeutic siRNA for cancer, CNS, and viral...
The retinoid-related orphan receptor gamma (RORgamma) is a member of the nuclear receptor superfamily. NIH investigators used homologous recombination in embryonic stem cells to generate mice in which the RORgamma gene was disrupted. RORgamma deficient mice lack peripheral and mesenteric lymph nodes and Peyer's patches indicating that ROR expression is indispensable for lymph node organogenesis. In addition, RORgamma is required for the generation of Th17 cells which play a critical role in autoimmune disease. The RORgamma deficient mice are useful to identify the physiological functions of the RORgamma. RORgamma deficient mice also provide an excellent tool to study the role of RORgamma in immune responses and autoimmune disease, the study of the role of Th17 and interleukin 17 in these processes, and the analysis. Source institute: NIEHS. Inventors: Jetten, Anton.
X-linked forms of retinitis pigmentosa (XLRP) are relatively severe blinding disorders, resulting from progressive photoreceptor dysfunction primarily caused by mutations in RPGR or RP2 gene. This technology is poised to advance RPGR or RP2 gene therapy to clinical stage using AAV8 or AAV9 vector carrying human full-length RPGR or RP2-coding sequence. The investigators have performed a wide dose range study over 18-months and found it to preserve rod and/or cone function as evidenced by ERG and/or OCT, optomotor tests. Morphologically, the treatment preserved rod and cone viability, and corrected mistrafficking of cone opsin and/or rhodopsin. The therapeutic effect was also achieved in advanced disease stage. The broad treatment window and long-lasting therapeutic effects make the RPGR and RP2 gene therapy attractive for clinical development. This technology is available for licensing, or the NEI research team will entertain potential...
Two isoforms of sphingosine kinase, sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2), convert sphingosine to sphingosine 1-phosphate (S1P) in mammalian cells. While the importance of SphK1 has been known for some time, information about SphK2 is still being revealed. Therefore, researchers at NIH have developed an antibody against mouse SphK2, which can be used to further understand the role of this enzyme. Commercial applications: The antibody can be used to detect and measure SphK2. Competitive advantages: The antibody works very well for western blotting. Source institute: NIDDK. Inventors: Proia, Richard.
The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. Researchers at NIH injected rabbits with the C-terminal peptide of the mouse S1P lyase — 551-TTDPVTQGNQMNGSPKPR-568 — to develop an antibody that can be used in western blotting to study this pathway. Commercial applications: The antibody can be used to detect and measure S1P lyase. Competitive advantages: The antibody works very well for western blotting. Source institute: NIDDK. Inventors: Proia, Richard.
Radio-sensitizing compounds for glioblastoma and other solid cancer Problem: Glioblastoma Multiforme (GBM), the most common primary brain tumor in adults, is an aggressive and locally invasive tumor. Despite advances in surgery, radiotherapy, and chemotherapy, overall survival of patients affected by GBM has only marginally increased from 6 to 14 months in recent decades. Use of conventional radiotherapy for treatment of GBM is limited by the dosage levels that can be applied to the tumor region without destabilizing the healthy neighboring cells. The efficiency of the treatment can be improved using radiation sensitizers that enhance the cytotoxic effects of radiations on the glioma cells, leading to improved therapeutic results. Solution: The Koumenis Lab at the University of Pennsylvania have devised a cell-based screening approach to identify novel radio-sensitizing compounds for GBM. Using a high throughput, unbiased screening...
Available for licensing are new methods of rapidly treating depression. The drugs currently used to treat depression work by increasing the activity at serotonin, norepinephrine and perhaps dopamine receptors in the CNS. However these drugs are effective in only 60-70% of patients, require 3-4 weeks of treatment before clinical improvement and have many side effects. These inventors have shown that in human patients, the administration of anti-muscarinic agents produces a rapid, prolonged alleviation of depressive symptoms. Beginning the day following administration of the anti-muscarinic agent, a majority of patients show significant improvements in mood, anxiety, sleep and other depressive symptoms that last days or weeks. The very slow dissociation of some muscarinic agents from their receptors may account for the prolonged therapeutic effects. Source institute: NIMH. Inventors: Drevets, Wayne.
The Zika virus (ZIKV) can be passed from a pregnant woman to her fetus. Resulting infection by this virus can cause early miscarriage and a pattern of severe birth defects in fetuses and infants. Therefore, a rapid diagnostic assay that can be performed throughout pregnancy in a clinical setting is vital for prenatal care of women living in areas where this virus may be transmitted. CDC has developed a RT-LAMP assay for the rapid screening of ZIKV RNA from urine and serum. As few as 10 copies of ZIKV RNA per microliter can be detected using this assay, showing that it is highly sensitive. It was also shown to be highly specific for ZIKV RNA when tested against a panel of urine samples spiked with other flaviviruses such as dengue virus sub-types 1-4, West Nile virus, St. Louis encephalitis virus, and chikungunya virus, most viruses that circulate in the same geographic regions as ZIKV. This assay offers a rapid, reliable, sensitive,...
One of the problems with the development of current therapies for HIV infection is that the virus rapidly develops resistance to drugs such as reverse transcriptase (RT) inhibitors. CDC researchers have developed an enzyme-based methodology for detecting phenotypic resistance to antiretroviral drugs whose mode of action decreases the efficiency of the HIV-1 RT enzyme. This invention will enhance clinical monitoring by providing data that tells physicians if and when the HIV-1 infecting a patient has become resistant to commonly used antiretroviral drugs, such as zidovudine/azidothymidine (AZT), nevirapine and lamivudine (3TC). This invention provides physicians and patient care facilities with a simple, rapid lab test that will tell them when a particular antiviral drug is not or no longer beneficial for a patient. Additionally this technology is superior to current culture-based methods for determining phenotypic resistance to HIV...
A platform technology to rapidly identify novel lipid nanoparticle (LNP) formulations to carry mRNA-based therapeutics to target organs/cells in vivo. Problem: Messenger RNA (mRNA) has emerged as a promising new class of nucleic acid therapy, with the potential to induce protein production to treat and prevent a range of diseases. While significant progress has been made in the design of in vitro-transcribed mRNA, the widespread use of mRNA as a therapeutic requires safe and effective delivery of the mRNA to tissues in vivo. Ionizable lipid nanoparticles (LNPs) are an emerging method to deliver mRNA to cells in vivo. However, targeting LNPs to deliver their mRNA cargo to a specific tissue of interest following intravenous injection has hampered their utility. Solution: This is a platform technology to screen for novel LNP formulations that optimize mRNA delivery to a desired cell type or organ in vivo. Inventors: Michael Mitchell,...
One-pot combinatorial chemistry for fast and facile synthesis of amidine-incorporated degradable cationic lipids for lipid nanoparticle formulation and non-liver nucleic acid delivery. Problem: Messenger RNA (mRNA)-based therapeutics and vaccines have broad applications for a variety of diseases but require safe and efficient delivery mechanisms. Lipid nanoparticles (LNPs) are widely used for mRNA delivery and require an essential cationic lipid component for protecting and transporting the nucleic acid cargo. Current methods of synthesizing cationic lipids require complex multi-step reactions, long incubations, or extreme temperatures. Synthesis of cationic lipids with quaternary or tertiary amines are especially laborious, limiting the discovery of novel lipid candidates and the ability to scale up LNP manufacturing. Moreover, traditional cationic lipid-formulated LNPs mainly target the liver, necessitating the development of novel...
This technology includes a system that allows for robust differentiation of human-induced pluripotent stem cells (iPSC) into motor neurons within a time frame of 7 to 10 days. To differentiate the iPSC, a stable transgene is inserted into the CLYBL safe harbor locus in the human genome using TALENs. The transgene allows for doxycycline-inducible expression of the transcription factors (NGN2, ISL1, and LHX3) that are needed for the cells to differentiate to motor neurons. The technology is described in detail in the protocol paper published by Fernandopulle et al, cited below. We knocked in a doxycycline-inducible transgene cassette into the CLYBI safe harbor locus of iPSCs using TALENs. The cassette drives expression of human NGN2, Isl1, and LXZH3, separated by 2A linker peptides. The targeting vector was a heavily-modified version of a CLYBL targeting vector from Mahendra Rao’s lab at the NIH (essentially, only the homology arms of...
The ability to easily detect small mutations in nucleic acids, such as single base substitutions, can provide a powerful tool for use in cancer detection, perinatal screens for inherited diseases, and analysis of genetic polymorphisms such as genetic mapping or for identification purposes. Current approaches make use of the mismatch that occurs between complimentary strands of DNA when there is a genetic mutation, the electrophoretic mobility differences caused by small sequence changes, and chemicals or enzymes that can cleave heteroduplex sites. Some of these methods, however, prove to be too cumbersome, are unable to pinpoint mutations, only detect a subset of mutations, or involve the use of hazardous materials. The current invention takes advantage of the ability of transposons, or mobile genetic elements, to move from one part of the genome to another by the cleavage and joining of their sequences into the target site; a...
Antibiotic resistance is one of the world's most pressing health concerns. ß-lactamases, such as carbapenemases, are enzymes produced by bacteria that provide resistance to multiple ß-lactam antibiotics (e.g., penicillins, cephamycins, and carbapenems) by breaking down the antibiotic molecules and deactivating their antibacterial properties. Carbapenems are broad-spectrum antibiotics often prescribed to treat serious infections in hospitalized patients, and infections with carbapenem-resistant Enterobacteriaceae (CRE) have become a challenge in healthcare settings. Clinical laboratories frequently use phenotypic tests to screen for carbapenemase-producing isolates. However, these phenotypic tests can be difficult to interpret and are unable to identify specific resistance genes. PCR can be utilized to detect the presence of specific resistance genes, such as IMP, and produces rapid results that are easily interpretable. To date, the...
Rabies occurs in more than 150 countries and territories, resulting in at least 55,000 human deaths per year worldwide according to World Health Organization estimates. Rabies is a vaccine-preventable viral disease caused by numerous lyssaviruses that are found in a variety of animal species throughout the world. Rabies virus infects the central nervous system, causing disease in the brain with almost 100% mortality once clinical symptoms manifest. Rapid and accurate laboratory diagnosis of rabies in humans and other animals is essential for timely administration of post-exposure prophylaxis. Due to significant sequence variation among rabies and related lyssaviruses, no single molecular diagnostic test detects all species that may cause fatal human rabies. Using modified nucleotide detection technologies, CDC scientists have developed a real-time RT-PCR assay that can detect all current known lyssaviruses (up to 15 species)...
Rickettsial infections are caused by bacteria from the Rickettsia genus which are often spread by biting ticks, fleas, mites or lice. Rickettsia can cause mild to severe illness and Rickettsia species can be found worldwide. Early stage, nonspecific symptoms of infections can make clinical diagnosis difficult. Rickettsial infection symptoms, if present, typically develop within 1 -2 weeks of exposure and include fever, headache, malaise, rash, nausea, and vomiting. Some rickettsial diseases such as Rocky Mountain spotted fever (RMSF), Mediterranean spotted fever, and typhus fever, can be life threatening and even fatal in 20% - 60% of untreated cases. Prompt identification of rickettsioses and treatment are essential. No vaccine is available for preventing rickettsial infections. CDC scientists have developed a Pan-Rickettsia genus (PanR6) real-time reverse transcriptase PCR (real-time RT PCR) assay targeting both rRNA and rDNA in...
Scrub typhus is a bacterial disease caused by Orientia tsutsugamushi (O. tsutsugamushi or Ots) that is spread to people through bites of infected chiggers (larval mites). The most common symptoms can include fever, headache, body aches, and sometimes rash. Severe illness can lead to organ failure and bleeding which can be fatal if left untreated. Most cases of scrub typhus occur in Asia Pacific countries, however, recent reports document establishment in the Arabian Peninsula, Chile, and possibly Kenya. Anyone living in or traveling to areas where scrub typhus is found could get infected if they come in contact with infected mites. Currently available DNA molecular tests lack sensitivity to reproducibly detect the low level of scrub typhus bacteria circulating in blood. CDC scientists developed a real-time reverse transcriptase PCR (real-time RT PCR) assay targeting both ribosomal RNA (rRNA) and ribosomal DNA (rDNA) in total nucleic...
Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and is also a frequent cause of bloodstream, brain and spinal cord, ear, and sinus infections. According to 2015 CDC data, an estimated 900,000 Americans get pneumococcal pneumonia each year and approximately 5-7% die from it annually. Accurate diagnosis and early treatment are important for improving patient outcomes. Pneumonia is typically diagnosed by clinical examination, chest X-rays, and culture of patient blood and secretions. X-rays cannot identify the pathogen; blood cultures take several days to grow with limited reliability; and sputum and throat culture specimens collected may not contain isolates of the organism. CDC researchers developed a Taqman-based assay that uses real-time PCR to detect three specific gene regions of S. pneumoniae with a very low limit of detection of 10 copies, and has shown high sensitivity and specificity against a...
This nucleic acid assay employs Light Upon Extension (LUX) chemistry and High Resolution Melt (HRM) analysis to detect and distinguish the different genotypes of Chlamydophila psittaci . C. psittaci is an atypical pathogen which may result in severe pneumonia upon infection of birds, mammals and humans (depending on inter-relationships between host and pathogen genotypes). Presently, C. psittaci clinical identification is achieved by a cumbersome and time-intensive mix of ompA gene sequencing, microarray analysis, RFLP and/or serological testing. Accurate and timely molecular C. psittaci diagnosis techniques are not generally available in most clinical facilities, leading to improper treatment of patients. To that end, this robust CDC developed assay should be useful for epidemiological studies and may provide valuable information for best implementing public health measures in the event of outbreaks. This tool may also offer greater...
Human Enterovirus D68 (EV-D68) is a non-polio enterovirus that can cause mild to severe respiratory illness, especially in infants and children with asthma. Since its identification, every year EV-D68 has been detected sporadically throughout the world. The US experienced a nationwide outbreak of EV-D68 associated with a particularly severe respiratory illness from mid-August to early November 2014, with 1,153 confirmed cases in 49 states and the District of Columbia. Although various established detection methods are available for EV-D68, enteroviruses evolve rapidly. New methods are needed for specific testing to determine which types of enteroviruses are circulating. CDC investigators have developed a real-time RT-PCR (reverse transcriptase – polymerase chain reaction) Taqman assay using primers and probes specific for EV-D68 viral protein 1 nucleic acid. This assay provides a more specific identification of EV-D68 strains allowing...
A quantitative RT-PCR-based assay has been developed to rapidly detect all known strains of Rift Valley fever virus (RVFV). RVFV infections occur in both humans and livestock animals resulting in significant mortality and economic loss. Upon outbreak, RVFV has been known to cause devastating loss among livestock (primarily sheep and cattle) with outbreaks characterized by sweeping "abortion storms" and elevation newborn animal mortality approaching 100% in affected areas. The CDC-developed assay is capable of detecting and quantifying RVFV infection in both human and veterinary samples. Commercial applications: Diagnostic assay for the detection of Rift Valley fever virus in human and veterinary samples. Research tool to quantitatively measure viral load in laboratory specimens. Competitive advantages: Assay detects positive infections for 33 known variants of Rift Valley fever virus.. Easily adaptable to kits for high-throughput...
Upon intranasal vaccination, live attenuated influenza vaccine (LAIV) viruses may replicate within the nose for several days. Current clinical diagnostic tests cannot distinguish between LAIV viruses and multiple influenza viruses in recently inoculated patients that present with respiratory symptoms. This poses a problem for the diagnosis and treatment of patients with respiratory symptoms, as these symptoms may not be caused by influenza. CDC researchers have developed a real-time RT-PCR assay to detect the presence of LAIV viruses. This test is rapid, accurate, and provides diagnostic data about whether patient respiratory symptoms are due to wild-type influenza or LAIV viruses. Detection of LAIV viruses with this assay will allow practitioners to investigate other pathogens as causative agents for a patient's respiratory symptoms. Commercial applications: Diagnostic assay for the discrimination of LAIV A and B viruses from the...
CDC scientists have developed recombinant flavivirus nucleic acids for the generation of broad protective immunity against flaviviruses, as well as the development of sensitive serologic diagnostic tools. Mosquito borne viral encephalitis is often caused by a flavivirus, such as Japanese encephalitis virus, dengue virus or West Nile virus. Infection by these pathogens is often lethal to both humans and animals. Specifically, these novel recombinant nucleic acids encode critical structural proteins of flaviviruses, such as yellow fever virus. The invention provides for a method of immunizing a subject against infection by a number of pathogenic flaviviruses. Furthermore, generated antigenic subviral particles can also serve as a tool for the development of specific, antibody detection-based flavivirus diagnostic assays. Commercial applications: Development of a broadly useful commercial vaccine for pathogenic flaviviruses. Insect-borne...
CDC researchers have developed recombinant lyssaviruses that can be used for the development of an improved, broad-spectrum vaccine against several rabies genotypes. Lyssaviruses are single-stranded RNA viruses that cause rabies and rabies-like diseases in mammals. Currently, there are commercially available vaccines that are considered to be effective against infections from a single viral phylogroup; however, these vaccines confer little or no protection against viruses outside of the phylogroup. The present recombinants have glycoprotein-encoding genes from at least two different lyssaviruses and can be used as pan-lyssaviral vaccines to provide protection against infection by multiple lyssavirus phylogroups. Commercial applications: Pan-lyssavirus vaccines. Rabies surveillance and vaccination programs. Competitive advantages: Broad-spectrum vaccine potential. Pan-lyssavirus vaccination tools will be particularly beneficial in...
CDC scientists have developed synthetic/recombinant polypeptides that can be used for the creation of inexpensive, high-quality cysticercosis diagnostic assays. Taenia solium is a species of pathogenic tapeworm. Intestinal infection with this parasite is referred to as taeniasis and it is acquired by ingestion of T. solium cysticerci found in raw and undercooked pork, or food contaminated with human or porcine excrement. Many infections are asymptomatic, but infection may be characterized by insomnia, anorexia, abdominal pain and weight loss. Cysticercosis is the formation of cysticerci in various body tissues resulting from the migration of the T. solium larvae out of the intestine. Although infection with T. solium is itself not dangerous, cysticercosis can be fatal. In the present invention, specific antigen encoding nucleotide sequences have been cloned; assays based on the produced antigens may be useful for improvements over the...
A Switchable Bispecific T-Cell Nanoengager (sBiTNE) to link T cells with cancer cells that can be reversed if off-tumor toxicity is detected. Problem: Compounds which link native T-cells with the surface antigens found on cancer cells have emerged as an effective treatment for blood malignancies and are currently being developed for solid tumors. However, many antigens are not only expressed on cancer cells, but also on healthy tissue, which can result in detrimental and even lethal toxicity when the T cells engage with and destroy healthy cells. Solution: This switchable bispecific T-cell Nanoengager (sBiTNE) is not only effective at engaging T-cells to cancer cells to facilitate their destruction, but upon discovery of adverse off-tumor toxicity, a small molecule amantadine (ADM) can be infused to destroy the sBITNEs and limit the damage. Inventors: Ningqiang Gong, Michael Mitchell.
Englerin A, a natural product, has shown growth-inhibiting activity against renal cancer cell lines. The compound is an agonist of protein kinase C (PCK) theta, which results in cell cytotoxicity, insulin inhibition, and selective activation of viral replication in T cells. Englerin A derivatives are promising treatment strategies for any diseases associated with PKC theta and/or ion channel proteins. Researchers at the National Cancer Institute have developed a series of Englerin A analogs for the treatment of renal cancer. The new derivatives are less toxic than the parent compound and have shown effective inhibition of growth in vitro. Competitive Advantages: PKC theta associated with a number of immune disorders, cancers, and HIV. Reduced toxicity compared to parent Englerin A compounds. Commercial Applications: Renal cancer therapeutic. HIV therapeutic. Source institute: NCI. Inventors: Beutler, John, Ransom, Tanya, Echavarren,...
Bone damage and/or fractures are common side effects of radiotherapy in cancer patients. Current treatments for radiation induced bone damage only reduce existing damage and can produce adverse side effects. On the other hand, sclerostin antibody repairs bone damage by facilitating repair of double strand breaks in DNA. Problem: Bone damage and/or fractures are common side effects of radiotherapy that pose a major health threat to cancer patients. Current treatments for radiation induced bone damage include teriparatide, raloxifine, bisphosphonates, and salmon synthetic calcitonin. These treatments inhibit bone resorption by suppressing osteoclast activity or triggering osteoclast death. Many of these approaches have adverse side effects, such as reflux disease, esophageal erosion, muscle aches, and cardiovascular events. Solution: In comparison to conventional treatments that simply reduce radiation damage, sclerostin antibody...
Mitigating ventilator-induced lung injury and acute respiratory distress syndrome through HER2/HER3 signaling pathway Problem: Acute lung injury, such as that induced by long-term treatment with a mechanical ventilator, and acute respiratory distress syndrome (ARDS) affects 190,000 patients per year in the United States, with associated mortality of 35-40%. The highest numbers of deaths are in patients with sepsis, pneumonia, or aspiration. ARDS is characterized by sudden breathlessness within hours to days of an inciting event, including trauma, sepsis, drug overdose, blood transfusion, and aspiration. ARDS is a life-threatening condition caused by widespread inflammation of the lungs that can lead to multisystem organ failure. Currently, there is no specific therapy for acute lung injury, and adjunctive strategies that modulate the deleterious effects of mechanical ventilation are needed. Solution: During mechanically-induced...
A respirator protects the wearer from inhaling dangerous substances, such as chemicals and infectious particles. CDC developed devices and methods to detect and remove chemicals such as hydrogen cyanide, cyanogen, hydrogen sulfide, nitrite, and nitric oxide from the air for those wearing respirators. Cobinamide (a Vitamin B12 analog with a high affinity to cyanide) molecules are immobilized within a silica matrix that allows for the infiltration and containment of gaseous chemicals. Since the chemical(s) bind to the cobinamide, such material is embedded into respirator canisters to help facilitate the removal of toxic molecules from the air. The chemical(s) binding to the cobinamide also result in a color change that can be analyzed qualitatively or quantitatively. The cobinamide-loaded silica matrix can be incorporated into a respirator canister (such as a canister designed to protect workers against chemical, biological,...
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for a class of novel aplithianine-derived small molecule analogs that compete with ATP for binding on a range of clinically relevant kinases including: Oncogenic gene fusion DNAJB1-PRKACA (PKADJ). Wild type protein kinase A (PKA) . Protein kinase G (PKG). Ccdc2-like kinases (CLK) 1 & 2. DYRK family of kinases. Description of Technology: In 2022, the NCI Molecular Targets Program (MTP) completed a screen of ~150,000 pre-fractionated natural products from the NCI Program for Natural Product Discovery (NPNPD). From this screen, a class of active compounds, named Aplithianines A & B (isolated from the marine organism Aplidium sp.) showed broad potential applicability to numerous kinases of importance including but not limited to: Oncogenic gene fusion DNAJB1-PRKACA (PKADJ) Implicated in an ultra-rare adolescent liver cancer. . Wild type...
Rare DiseaseOncologyInfectious DiseaseImmunologyNeurologyCardiometabolicBiologicSmall MoleculeAI / ML
NIAID scientists have developed plasmids that allow for production of pseudoviruses expressing SARS-CoV-2 spike protein. As SARS-CoV-2 is a lethal airborne virus, it must be handled in high-containment Biosafety Level 3 (BSL-3) laboratories that require strict airflow, ventilation and decontamination procedures. The pseudotyping plasmids of this invention provide a secure platform for exploring SARS-CoV-2 dynamics without the need for high-risk handling of live virus and ensure a controlled environment for scientists to study SARS-CoV-2 more expeditiously in standard Biosafety Level 2 (BSL -2) laboratories. The plasmids can be used for diverse SARS-CoV-2 research applications, including the study of newly emerging or potential future variants of interest. Commercial applications: Research material that can be used in the development of neutralization assays. Competitive advantages: Expedite SARS-CoV-2 related experiments by enabling...
The emergence of the SARS-CoV-2 virus and its immune-escaping variants have led to global COVID-19 pandemic/endemic, underscoring the urgent need for effective vaccines with strong and durable immune responses. Researchers at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID) used a novel approach to SARS-CoV-2 vaccine development by leveraging hepatitis B surface antigen (HBsAg), which has a proven track record of safety and efficacy in hepatitis B vaccines. They designed fusion protein constructs comprised of HBsAg linked by a series of glycine-serine residues to the prefusion stabilized spike protein of SARS-CoV-2. These constructs can self-assemble into nanoparticles in mammalian cells and bind monoclonal antibodies (mAbs) that are specific to different domains of the SARS-CoV-2 spike. The nanoparticles elicit potent and durable immune responses including neutralizing antibody...
SIRT1, a NAD+-dependent protein deacetylase, is the most conserved member of the sirtuins family. Through deacetylation of a number of protein substrates that are important transcription factors or co-factors, SIRT1 regulates many vital biological processes such as metabolism, cellular stress response, stem cell pluripotency, and development. The present invention describes SIRT1 KO human cell lines in three different cell types generated by using the CRISPR/Cas9-hSIRT1 DNA editing constructs designed and provided by Horizon Discovery, a UK based biotechnology company. The cells lines can be used to elucidate the role of SIRT1 in human and to screen for SIRT1 activators or inhibitors that have potential therapeutic applications in a number of human diseases, such as diabetes, inflammatory bowel diseases, and cancer. Commercial applications: SIRT1 KO human cell lines can be used to investigate the role of this protein in a wide variety...
Using mRNA-LNPs to deliver forkhead box protein 3 (Foxp3) to CD4+ T cells to engineer Foxp3-positive T (FP3T) cells with immunosuppressive properties. Problem: Autoimmune disorders (e.g., type 1 diabetes, multiple sclerosis, and myasthenia gravis) are mediated by self-reactive lymphocyte (B or T cells) expansion. Available suppressive medications like steroids, require frequent dosing and are non-specific, resulting in systemic immunosuppression and increased susceptibility to infections. Adoptive cell therapy is a safer and targeted alternative as it utilizes patient-derived cells to achieve immunosuppression and limits extreme side effects such as cytokine release syndrome. Specifically, regulatory T cells (Tregs) have gained attention due to their critical role in immunosuppressive modulation. However, harvesting, purifying, and growing Tregs to therapeutically relevant numbers is challenging. Solution: The inventors identified a...
Despite therapeutic advances, human immunodeficiency virus (HIV) is still a pervasive disease, with approximately 37 million people infected worldwide. Peptides have become popular therapeutic agents, as these proteins offer structural diversity for many different diseases. Several peptides were commercially developed as HIV therapeutics, demonstrating the high potential for peptides in treating HIV. Researchers at the National Cancer Institute developed a novel small polypeptide, known as SD1, for use as an HIV therapeutic. SD1 is derived from scytovirin, a potent anti-HIV protein isolated from the cyanobacterium Scytonema varium. SD1 has demonstrated low nanomolar activity against laboratory HIV strains and inhibits HIV by blocking viral fusion. SD1 is a lectin with specificity for viral envelope glycoproteins. Competitive Advantages: Small size allows for decreased immunogenicity. Small size allows for easy synthesis using...
This CDC-developed technology relates to novel vaccines or boosters directed against pulmonary tuberculosis. There is currently only a single vaccine against tuberculosis, the (Bacillus Calmette-Guérin) BCG vaccine. Reports suggest widely variable effectiveness for the BCG vaccine and that BCG administration has very limited success against prevention of the primary pulmonary form of the disease. With a marginally useful vaccine and rising rates of multidrug-resistant and extensively drug-resistant (MDR and XDR) tuberculosis strains, it is clear there is a public health need that must be met. Researchers working at CDC have developed improved vaccine formulations and processes of delivery for enhancing the immune response against M. tuberculosis . These improvements may be implemented as stand-alone vaccines or in conjunction with BCG as part of a prime-boost strategy. Intranasal immunization engenders a strong immune response in the...
This invention discloses small molecule inhibitors of human 12-lipoxygenase (12-hLO). 12-lipoxygenase expression, activation, and lipid metabolites have been implicated in type 1 and type 2 diabetes, cardiovascular disease, hypertension, Alzheimer’s, and Parkinson’s disease. The development of 12-hLO inhibitors may be a potent intracellular approach to decreasing the ability of platelets to form large clots in response to vessel injury or activation of the coagulation pathway. Thus, 12-hLO inhibition has the potential to attenuate platelet-mediated clot formation caused by diabetes and/or cardiovascular disease and significantly decrease the occurrence of myocardial infarction and death. Moreover, Type 1 and Type 2 diabetes are serious disorders that can lead to major complications and reduced lifespan. An unmet medical need is to identify new ways to protect beta cells in these metabolic disorders. A selective 12-hLO inhibitor could...
This technology includes the creation and use of A3 adenosine receptor (A3AR)-selective agonists for treating chemotherapy-induced peripheral neuropathy, chronic neuropathic pain, rheumatoid arthritis, psoriasis, and other conditions. A3 receptors for adenosine are found in most cells and endogenous activation of the A3 receptors can result in apoptosis, thereby relieving the inflammation or targeting a tumor. A3AR agonists have been a promising strategy for the treatment of various diseases. A3AR agonists can reverse neuropathic pain by modulating the production of anti-inflammatory cytokines such as IL-10. A3AR agonists can also induce apoptosis of cancer and inflammatory cells by disrupting the Wnt and NF-KB signaling pathways. The current invention includes A3AR-selective agonists that are methanocarba derivatives. This class of compounds has been shown to be highly selective for A3AR (>3000-fold affinity versus A1AR and A2AAR)....
Summary: The National Cancer Institute (NCI) seeks capable licensees interested in commercializing T cell receptor (TCR)-engineered T cells expressing murine/human hybrid receptors. Description of Technology: TCR-T therapies, particularly those targeting patient-specific neoantigens, remain a promising approach to the treatment metastatic cancers. Contemporary gene engineering techniques permit both the targeted integration of the exogenous receptor(s) and further genetic manipulation of the host cells to enhance persistence and performance following adoptive transfer (e.g., through disruption of immune checkpoints such as CISH or PD1). However, these techniques often suffer from low transduction efficiencies and may result in the generation of infusion products with sub-optimal percentages of targeted cells. NCI scientists designed a new method that enables the selective expansion of T lymphocytes, under GMP conditions, that have...
Small-molecule compositions modulate non-canonical sex steroid receptors to decrease, prevent, or reverse skin pigmentation gain in mammalian subjects. Problem: Skin hyperpigmentation can arise from pregnancy, hormones, inflammatory conditions, or skin injury. Existing approaches may not address receptor pathways that regulate melanocyte pigmentation. Melanin reduction methods also need formulations suitable for skin delivery. Improved compositions are needed for localized treatment of pigmentary skin changes. Solution: The technology uses compounds that antagonize GPER or agonize PAQR7 to modulate skin pigmentation. These compounds are formulated in pharmaceutical compositions for topical or transdermal administration. In some embodiments, the compounds do not bind canonical nuclear estrogen or progesterone receptors. The compositions are described for decreasing, preventing, or reversing gain of skin pigmentation. Applications:...
Retinal degeneration is a deteriorative condition of the human retina caused by the progressive and eventual death of photoreceptor cells. To date, no effective treatment for genetically inherited or age-associated retinal degeneration, which includes a large patient population worldwide, is available. Researchers at the National Eye Institute (NEI) have discovered a novel therapeutic strategy of using one or more SERMs compounds, which may include the FDA-approved drug, Tamoxifen, for treating retinal degenerative diseases, like retinitis pigmentosa (RP) and age-related degeneration (AMD). SERMs exert their specific protection on photoreceptor degeneration likely by inhibiting microglial activation. Commercial entities who are interested in developing new drugs for ocular disorders are being actively sought for co-developing this technology as collaborative partners or licensing it for commercialization. Competitive Advantages: There...
Cell therapy based methods to reduce tumor growth by disrupting the CD47-SIRPα interaction and targeting cells for phagocytosis with antibodies. Problem: Current cancer treatments (i.e. radiation, chemotherapy, etc.) result in multiple serious side effects due to lack of treatment specificity. Cancer immunotherapies in development target the CD47-SIRPα interaction in order to incite local macrophages to engulf cancer cells, but tumor associated macrophages in solid tumors do not exhibit strong anti-tumor properties. In addition, CD47 is abundant on all healthy cells, so that targeting CD47 will generally harm healthy cells and lead to a variety of unwanted side effects such as anemia. A therapy that enhances macrophage phagocytosis specifically of tumor cells and also avoids broad targeting of CD47 will reduce tumor size without the complications of current treatment regimens. Solution: The Discher Lab has developed a method to...
Peptides corresponding to transmembrane domains of a number of integral proteins were discovered to spontaneously self-assemble in aqueous solutions into stable and remarkably uniform nanoparticles. Researchers at the NCI’s Cancer and Inflammation Program have developed fully synthetic, peptide-based, virus-like nanoparticles capable of delivering cytotoxic, radioactive, and imaging agents. Structure and function of tumor-target self-assembling particles: The current invention discloses peptide based fusogenic virus-like nanoparticles that can be targeted to tumors. The nanoparticles have a diameter of 8-10 nm and, being much smaller than a liposome, demonstrate better tumor penetration. The body of the nanoparticle is comprised of a G-protein coupled receptor or an ABC transporter antagonist. The technology solves the problem of delivering therapeutic, theranostic and imaging agents – and is an alternative to liposome-based...
CDC research scientists have developed a method to identify and quantify the activity of pathogenic bacterial adenylate cyclase toxins by liquid chromatography tandem mass spectrometry (LC-MS/MS). Bacterial protein toxins are among the most potent natural poisons known, causing paralysis, immune system collapse, hemorrhaging and death in some cases. A useful tool for quantitative detection of specific toxin activity in clinical samples will provide insights into the kinetics of intoxication, stage of infection and present stage of pathogenesis. This rapid, high-throughput analysis method will provide measurements that quantify the efficacy of toxin-based therapeutics and support patient management decisions during treatment. This technology is specific, ultrasensitive and can be implemented to detect toxins from a wide range of pathogenic bacteria. This method could be fabricated into a kit format to deliver to state or research...
Infectious DiseaseImmunologyCardiometabolicBiologicDiagnostic / BiomarkerAI / ML
Serotonin is an important modulator of many developmental, behavioral, and physiological processes, and it has been implicated in depression, anxiety, schizophrenia, obsessive compulsive disorders, and substance abuse. Serotonin’s pharmacology is extremely complex and it is mediated by seven of serotonin receptor subtypes and it is present in several tissues. Although it has been a subject of a number of studies, its role has been difficult to ascertain. To investigate the role of serotonin in these disorders, the murine gene was disrupted by homologous recombination. Results indicate that serotonin binding sites were absent in different brain regions (brain stem, frontal cortex, hippocampus, and striatum), and its concentrations were reduced by 60-80%. These mice represent a powerful tool for the investigation of behavioral and neuropsychiatric disorders, and development of drug treatments for these disorders. Commercial...
Our technology describes unique genetic signatures in patients with digestive diseases and liver disorders. Using comprehensive analysis of 735 microRNAs and 19,000 mRNAs, we have identified a unique set of microRNAs and/or mRNAs which predict disease phenotypes in patients with digestive and liver disorders. The identification of such point-of- care genetic signatures is significant for both personalized biomarkers and novel targeted biotherapeutics. These microRNAs and mRNAs function either together or separately thus modulating protein expressions in one or more signaling pathways. A particular noteworthy signature of genetic control includes miR-150, which is known to modulate target proteins within the Akt signaling pathways implicated in inflammatory processes as well as processes affecting cancer cell proliferation and/or survival. Commercial applications: Personalized biomarkers. Novel targeted biotherapeutic. Competitive...
Viral vector-mediated gene silencing of a novel short retinal isoform of Prolactin promotes photoreceptor survival. Problem: Age-related macular degeneration (AMD) and inherited retinal degeneration (IRDs) have extreme mutational heterogeneity, and many IRDs are orphan diseases. Developing individual gene therapies for each causative gene is impractical and cost-ineffective. Therefore, developing universal therapeutic options that can prolong photoreceptor survival for various forms of retinal degeneration remains the holy grail for treating IRDs and AMD. Solution: The inventors have identified a novel isoform of full-length prolactin (PRL) lacking the first exon, PRLΔE1, expressed explicitly in diseased rod photoreceptors. An shRNA-mediated gene therapy designed to knockdownPRLΔE1 demonstrates an initial protective effect in the retina, supporting PRLΔE1 knockdown as a candidate strategy for a “gene agnostic” therapy for retinal...
Simian T-cell lymphotropic viruses (STLV) are nonhuman primate retroviruses closely related to the human T-lymphotropic virus (HTLV). Types I, II, and III of HTLV have been found in humans and are believed to have originated from cross-species transmission of STLV from infected nonhuman primates. The HTLV viruses are known to cause leukemia, lymphoma, and neurological disorders. CDC researchers discovered a strain of simian T-cell lymphotropic virus type 3 known as STLV-3 subtype D variant. STLV-3 may be widespread in primates hunted in West-Central Africa, including the monkey Cercopithecus mona, which has a known geographic habitat range from Ghana to Cameroon. This increases the risk to hunters and persons in contact with primate bushmeat for infection with STLV-3-like viruses. Thus, the discovery of the highly divergent STLV-3 subtype D variant implies that a similar virus (HTLV-3) subtype D variant could be spreading undetected...
Within recent years, point-of-care (POC) testing has allowed for many individuals to be screened for and provided with HIV test results. It is critical to be able to accurately detect acute HIV infections as this is a stage where the risk of transmission is great. Additionally, early HIV detection could lead to less high-risk behavior, thereby reducing transmission. Currently, there are no rapid, cost-effective diagnostic tests sensitive enough to detect acute HIV-1 infections for the POC setting. Researchers at the CDC have developed an HIV-1 detection assay using reverse-transcription loop-mediated isothermal amplification (RT-LAMP) that is quick, easy to perform, and does not require complex, dedicated equipment or laboratory space. These features are ideal for POC and could increase the percentage of individuals who receive their HIV status, while immediately linking them to counseling and medical care. Also, the early knowledge...
Mycoplasma pneumoniae (M. pneumonia) can cause several different types of infection including chest colds and pneumonia. M. pneumoniae is a leading cause of community-acquired pneumonia. People of all ages are at risk for getting M. pneumonia infection, but it is most common among young adults and school-aged children. Current methods of detecting this agent are laborious and time consuming, so testing is not usually performed. However, knowing whether someone has M. pneumoniae infection is important for choosing the right antibiotic for treatment. Although real-time PCR assays exist for detecting this pathogen, they require sophisticated and expensive machinery as well as specialized technical expertise. CDC researchers have developed a simple loop-mediated isothermal amplification (LAMP)-based assay to detect this pathogen. This method only requires a simple heat block and is an easy-to-read colorimetric assay. The technology is...
CDC researchers have developed improved Loop-Mediated Isothermal Amplification (LAMP) assays for the nucleic acid-based diagnosis of malaria in field settings. The approach employs Plasmodium genus-specific LAMP primers and a portable tube scanner to run the LAMP reaction and measure fluorescence signal (e.g., SYBR green) as a measure of DNA amplification in real time. Using this platform, the researchers were able to detect several different species of the human malaria parasites. This LAMP approach has demonstrated the ability of this assay to detect P. falciparum in clinical samples with approximately 99-100% sensitivity, an improvement over standard nested PCR methodology. Additionally, DNA extracted by direct boiling of whole blood works well in this assay. Further, several important practical aspects of the method make it an attractive method for on-site uses. For example, it is portable to remote locales, required equipment is...
This novel assay features real-time PCR reagents and methods for detecting drug-resistance related mutations in HIV, for newly diagnosed patients and those individuals currently receiving antiretroviral therapies. As the use of antiretroviral compounds to treat HIV infection proliferates, viruses adapt and evolve mutations limiting the efficacy of these drugs and disrupting the success of treatment. To address this problem, CDC researchers have developed this RT-PCR assay, intended for diagnosis of different point mutations in patient samples at an achievable sensitivity of 1-2 log greater than conventional point-mutation sequencing methods. More specifically, this assay measures the differential amplifications of common and mutation-specific reactions that target specific codons of interest. Given its low cost, simplicity, high-throughput capability, and tremendous diagnostic sensitivity, this assay will be useful for detection and...
OphthalmologyOncologyInfectious DiseaseCardiometabolicInflammationSmall MoleculeDiagnostic / BiomarkerAI / ML
Summary: The NCI seeks licensing and/or co-development research collaborations for SARS-CoV-2 targeting nanobodies. Description of Technology: The COVID-19 pandemic is a worldwide public health crisis with over 100 million confirmed cases and 2.4 million deaths as of February 2021. COVID-19 is caused by a novel coronavirus called SARS-CoV-2. SARS-COV-2 infects hosts via its spike (S) protein. The S protein contains the receptor binding domain (RBD) that binds to the angiotensin converting enzyme 2 (ACE2) receptor on human cells to facilitate viral entry and infection. There are few therapeutics available for COVID-19 patients that directly target SARS-CoV-2. Investigators at the National Cancer Institute (NCI) have isolated a panel of anti-RBD single domain antibodies (also called ‘nanobodies’) from camel single domain (VHH) phage display libraries. RBD is an ideal target as it is the key virus-host contact region required for viral...
Description: The COVID-19 pandemic is a worldwide public health crisis with over 100 million confirmed cases and 2.4 million deaths as of February 2021. COVID-19 is caused by a novel coronavirus called SARS-CoV-2. Almost all the neutralizing antibodies targeting SARS-CoV-2 that are in development recognize the receptor binding domain (RBD) on the spike (S) protein. Blocking the interaction of RBD and the ACE2 receptor on human cells is the first of the two critical steps for neutralization of the virus. However, the S2 subunit of the spike is also critical for viral infection and entry into human cells. It is highly conserved across many coronaviruses, including other SARS-CoV-2 like viruses. To date there are no antibodies targeting the S2 subunit. Potential Commercial Applications: Treatment of SARS-CoV-2 infections. Standard antibody therapy. Delivery of nanoparticles. Competitive Advantages: Currently, only one antibody treatment...
Description of Technology: Human papillomavirus (HPV) has been linked to many cancers including cervix, uterine, anus, vulva, vagina, and penis. Although HPV vaccines exist to prevent HPV-associated cancers, there are still more than 5,000 deaths caused by HPV-associated cancers each year in the US and cervical cancer continues to be the second leading cause of cancer death in women ages 20 to 39. Engineered T cell receptor (TCR) therapy has been effective in some patients with HPV16 E6 expressing cancers, however, there continues to be a need for more therapies targeting HPV16 E6, when current treatment options fail. NCI inventors have identified two nanobodies (F5 and G9) against MHC/E6 by phage display technologies from the lab’s multiple dromedary camel VHH single domain libraries. F5 and G9 could recognize the MHC/E6 complex more specifically over the control nanobodies. CAR T cells using the F5 nanobody as the binding domain...
Soluble forms of human CD4 (sCD4) inhibit HIV-1 entry into immune cells. Different forms of sCD4 and their fusion proteins have been extensively studied in animal models and clinical trials as promising HIV-1 inhibitors. However, they have not been successful in clinical trials due to their transient efficacy. sCD4 is also known to interact with class II major histocompatibility complex (MHCII) and, at low concentrations, could enhance HIV-1 infectivity. NCI researchers developed highly soluble, stable single-domain sCD4 with increased neutralizing activity and decreased non-specific binding compared to two-domain sCD4. This invention describes this single-domain sCD4, designated D1, and mutants such as mD1.22 which is highly soluble and stable with good neutralizing activity without measurable interaction with MHCII. The inventors have previously described a novel human domain antibody against HIV-1, designated m36. Due to its small...
A single lentiviral vector system as an expression platform for constitutive immune receptor expression and inducible antigen-dependent immunomodulatory molecule expression in primary immune cells for enhanced immunotherapy efficacy Problem: Adoptive cancer immunotherapy, like chimeric antigen receptor T cell (CAR T) therapy, has had extraordinary clinical outcomes in the treatment of certain blood cancers. However, challenges remain due to safety risks such as cytokine release syndrome (CRS) and off-tumor toxicities. Targeting solid tumors is challenging due to immunosuppressive mechanisms and a hostile tumor microenvironment. Therefore, more advanced engineered T cells are necessary to improve targeting, localization, and autonomous regulation in hopes of overcoming the immunosuppression of the microenvironment to improve the efficacy and safety of cancer immunotherapy. Solution: Dr. Powell and colleagues have developed a novel,...
The National Cancer Institute seeks parties to license human monoclonal antibodies and immunoconjugates and co-develop, evaluate, and/or commercialize large-scale antibody production and hepatocellular carcinoma (HCC) xenograft mouse models. An advantage of these monoclonal antibodies as a potential therapeutic is their specificity, which would reduce deleterious side-effects. HCC is the most common form of liver cancer, and is among the more deadly cancers in the world. There is a need for new treatments that can be successfully applied to a large population of patients. Glypican-3 (GPC3) is a cell surface protein that is preferentially expressed on HCC cells.Researchers at the NCI Laboratory of Molecular Biology demonstrated that a soluble form of GPC3 that is incapable of cell signaling can inhibit the growth of HCC cells. This suggests that blocking GPC3 signaling could serve as a therapeutic approach for treating HCC. This...
Sirt1 knockout: Sirt1, a protein deacetylase, is a tumor suppressor that promotes genome stability and regulates proteins involved in energy metabolism. Yeast Sir2, a nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, has been implicated in chromatin silencing, longevity and genome stability. Mammals contain a family of related deacetylases, the sirtuins, of which 7 have been identified. Sirt1 is the closest mammalian orthologue of yeast Sir 2. The Sirt1 gene in mice was disrupted by homologous recombination in embryonic stem cells. The majority of Sirt1 (-/-) embryos die between E9.5 and E14.5, displaying altered histone modification, increased chromosomal aberrations, and impaired DNA damage repair. Tumor formation was increased in mutant tissues in Sirt1(+/-): p53(+/-) double heterozygotes, indicating that full levels of Sirt1 are necessary for tumor suppression. Tumorigenesis is reduced by treatment with the...
Generation of floxed Sirtuin 1 Exon5-Exon6 for the construction of conditional knockout mice. Sirtuin 1 (Sirt1), a homolog of yeast Sir 2, is an NAD-dependent histone and protein deacetylase. It has a wide range of biological functions, ranging from DNA damage repair to effects on glucose metabolism. Sirt1 null mice die before birth due to chromosomal aberrations and impaired DNA damage repair. Sirt1 is thought to affect energy metabolism, but the mechanism remains poorly understood. In order to study tissue-specific metabolic effects of Sirt1, floxed Sirt1 was constructed so that exons 5 and 6 would be deleted using the Cre-Lox strategy. In contrast to a previously reported deletion of Sirt1 exon4, no truncated (and potentially active) Sirt1 forms were detected when exons 5 and 6 were deleted. Hepatic exon 5-6 null Sirt1 mice were generated when Floxed Sirt1 exon 5 and 6 mice were mated with mice that expressed the Cre-recombinase in...
Sirt3 knockout: Sirt3 is a mitochondrial-localized tumor suppressor that maintains mitochondrial integrity and metabolism during stress. Sirt3 is a mitochondrial protein that is a member of the Sirtuin family of NAD-dependent protein deacetylases. Sirt3(-/-) mice are phenotypically normal, but exhibit many proteins whose acetylation is increased. They generate more reactive oxygen species and are more susceptible to mammary tumors than normal mice. Sirt3 is inactivated in a large percentage of human breast and ovarian cancers, suggesting that Sirt3 may be a mitochondria-localized tumor suppressor by maintaining mitochondrial integrity and efficient oxidative metabolism. Commercial applications: Cardiology. Metabolism. Source institute: NIDDK. Inventors: Deng, Chuxia.
Generation of floxed Sirtuin 6 for the construction of conditional knockout mice. The Sirtuins (Sirt1-7), a family of seven proteins related to yeast Sir2, are histone deacetylases that regulate many critical biological processes including genomic stability, adaptation to calorie restriction and aging. Mice with a targeted disruption of Sirt6 had very low levels of blood glucose (and paradoxically, low insulin levels) and died shortly after weaning. Hypoglycemia, attributed to increased sensitivity to insulin, was the major cause for lethality. Because of the post-weaning mortality of Sirt6 null mice, liver-specific Sirt6 conditional knockout mice were constructed using Cre-Lox technology to study the effects on glucose and lipid metabolism. Hepatic-specific Sirt6 deficient mice exhibited increased glycolysis and triglyceride synthesis, resulting in the development of fatty liver. Sirt6 is a potential therapeutic target for treating...
Synthetic oligonucleotides blocking natural degradation of utrophin to treat muscular dystrophy. Problem: Duchenne Muscular Dystrophy (DMD) is a severe form of muscular dystrophy affecting males. A genetic mutation causes decreased production of dystrophin, a critical protein connecting cells to surrounding tissue. This leads to improper muscle development and muscle loss. Patients suffer from motor and respiratory impairment, and many people afflicted with DMD do not survive beyond their 20s. One strategy to treat DMD is to increase utrophin, a protein with similar structure and function to dystrophin. However, current strategies to artificially upregulate utrophin have not progressed clinically, because they fail to prevent the natural degradation of utrophin mRNA following transcription. Solution: The solution is a set of synthetic site-blocking oligonucleotides (SBO) which inhibits natural degradation of utrophin mRNA. These SBOs...
Smad4 knockout: Smad4 is essential for epiblast proliferation, egg cylinder formation and mesoderm induction in early embryogenesis. The TGF-beta-related superfamily plays an important role in multiple biological systems including embryogenesis. TGF-beta ligands activate specific receptors, which interact with specific Smad proteins, which in turn form a complex with a common partner, Smad4, that conveys the signal to downstream targets. Exon 8 of the Smad4 gene was disrupted using homologous recombination in embryonic stem cells. Exon 8 encodes the C-terminal domain of Smad4 that is essential for the formation of heteromeric complexes with the other Smads. Mice heterozygous for the Smad4 mutation are phenotypically normal. Homozygotes, however, die early in embryonic development (day E6.5-8.5). Smad4 is required for three essential functions in early embryogenesis: epiblast proliferation, egg cylinder formation, and mesoderm...
The invention pertains to the use of glucan encapsulated non-immunostimulatory small interfering RNAs (siRNAs) to treat type-2 diabetes. Endocannabinoids (EC) are lipid signaling molecules that act on the same cannabinoid receptors that recognize and mediate the effects of endo- and phytocannabanoids. EC receptor CB1R activation is implicated in the development of obesity and its metabolic consequences, including insulin resistance and type 2 diabetes. Beta-cell loss has been demonstrated in a Zucker diabetic fatty (ZDF) rat model of type-2 diabetes through CB1R-mediated activation of a macrophage-mediated inflammatory response. Conversely, rats treated with a peripheral CB1R antagonist restores normoglycemia and preserves beta-cell function. Similar results are seen following selective in vivo knockdown of macrophage CB1R by daily treatment of ZDF rats with the instant D-glucan-encapsulated CB1R Small interfering RNA (siRNA)....
NIH investigators have discovered a series of small compounds with the potential to treat a variety of cancers as well as hemolytic anemia. Contrary to most cancer medications, these molecules can be non-toxic to normal cells because they target a protein specific to the metabolic pathways in tumors, thus representing a significant clinical advantage over less-specific chemotherapeutics. The invention described here is a series of small molecules that activate pyruvate kinase (PK) isoform M2. PK-M2 is a critical metabolic enzyme that is affected in all forms of cancer. Inactivation of PK-M2 leads to a buildup of metabolic intermediates inside the cell. Tumor cells require a buildup of metabolic intermediates in order to undergo rapid cell growth and proliferation. Hence, activation of PK-M2 in tumor cells may prevent the buildup of metabolic intermediates and thereby stall tumor cell proliferation or destroy the tumor cells. Further,...
The proto-oncogene c-Myc is deregulated and overexpressed in ~70% of all cancers. Thus, c-Myc is an attractive therapeutic target since disrupting c-Myc activity could be used as pan-chemotherapy. Beyond cancer, Myc is also a positive effector of tissue inflammation, and its function has been implicated in the pathophysiology of heart failure. Because c-Myc is a transcription factor, a rationally designed small molecule targeting c-Myc would be required to exhibit significant specificity. Unfortunately, several physical characteristics of Myc make it a very difficult protein to target and, to date, there are no approved drugs targeting c-Myc. The invention is directed to small molecules that stabilize the transcription repressing quadruplex in the c-Myc gene promoter region. Invention compounds target c-Myc at the transcriptional level are shown to inhibit c-Myc expression. Invention compounds are effective in selective killing in a...
Antiviral compounds that competitively disrupt virus-host interactions to inhibit disease progression and transmission Problem: Hemorrhagic fever viruses such as Ebola, Marburg, and Lassa are some of the deadliest viruses in the world and yet, there are currently no vaccines or therapeutics available to control their infection and transmission. The 2014 Ebola outbreak had devastating effects on the economies, healthcare systems and communities in the West African countries of Sierra Leone, Guinea and Liberia. This outbreak also had an impact on the U.S. economy, with $2.4 billion dollars (the most from any country worldwide) being donated in the form of personnel, technical expertise and resources to establish three new emergency operation centers to control the epidemic (CDC). While the number of hemorrhagic fever incidences has declined since 2014, a broad spectrum antiviral that is effective at controlling these viruses is urgently...
Description of Technology: Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. Ephrin (Eph) receptors are a clinically relevant class of receptor tyrosine kinases. Related signaling pathways are associated with oncogenesis of a number of cancers. NCI investigators found that phosphotyrosine-dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. Furthermore, colorectal cancers express the EphrinB2 ligand and its Eph receptors at significantly higher levels than numerous other cancer types. Colorectal cancer patients with the highest levels of EphrinB2 expression in their tumor have a lower probability of survival than those with the lowest levels. The NCI investigators found that a small-molecule inhibitor of the Eph kinase, NVP-BHG712 and its regioisomer NVP-Iso, reduce human colorectal cancer...
Innovative approaches to combat antibiotic resistance and enhance efficacy of existing antibiotics, particularly against biofilm-encased and persister bacteria.
Integrase strand transfer inhibitors (“INSTIs”) are currently in use as a component of prophylactic antiretroviral therapy for preventing HIV-1 infection from progressing to AIDS. Three INSTIs are approved by the FDA for inclusion in antiretroviral regiments: raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). Clinicians have already identified several HIV-1 integrase mutations that confer resistance to RAL and EVG, and additional mutations that confer resistance to all three INSTIs has been identified in the laboratory. Researchers at the National Cancer Institute discovered small-molecule compounds containing 1-hydroxy-2-oxo-1,8-naphthyridine moieties whose activity against HIV-1 integrase mutants confer resistance to currently approved INSTIs. These new compounds exhibit potent and selective activity against comprehensive and varied panels of INSTI-resistant mutants of HIV-1 integrase. Preliminary metabolic and...
Description of Technology: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and makes up 3% of all childhood cancers. Aveloar Rhabdomyosarcoma is the most aggressive subtype and is primarily established through a chromosomal translocation resulting in the fusion protein PAX3-FOXO1. Despite aggressive therapy, the 5-year survival rate for patients with high risk or recurrent Fusion Positive RMS (FP-RMS) is low (~30% and ~17%, respectively). Therefore, new therapies targeting the PAX3-FOXO1 oncogenic driver are urgently needed. To identify inhibitors of PAX3-FOXO1, scientists at the National Cancer Institute (NCI) developed a novel cell-based reporter assay of PAX3-FOXO1 activity. Using this system NCI scientists screened a 62,643 small molecule chemical library and found compounds with unknown function that disrupt PAX3-FOXO1 activity. Further studies of these compounds showed that they were inhibitors...
Small molecule inhibitors of a key cancer cell signaling pathway cause hematologic cancer cell death, but have low toxicity towards healthy cells. Applications: Treatment of primary hematologic malignancies Treatment of relapsed and refractory hematologic malignancies Inventors: Yanming Du, Wafik El-Deiry, Yonggang Pei, Erle Robertson.
This technology uses small molecules to bind HIV Env on infected cells, expose hidden sites, and trigger ADCC, enabling the immune system to kill cells that current therapies cannot reach. By improving antibody recognition and reducing infectious virus production, it provides a complementary approach that directly targets infected cells rather than only preventing new infections. Problem: Most HIV therapies stop new infections but do not remove cells that are already infected. Persistent infected cells allow ongoing viral production and disease progression. Clinicians and researchers therefore need treatments that directly identify and eliminate infected cells rather than only blocking new viral entry. One promising path is antibody-dependent cell mediated cytotoxicity (ADCC), where infected cells are marked for immune destruction through cell-surface recognition. Solution: Small molecules act as targeting agents that attach to...
Problem: There is a need for new therapeutics that prevent cardiovascular diseases with minimal effects on normal blood clotting. Integrin α2β1 is a good therapeutic target since it can lead to cardiovascular diseases including stroke or myocardial infarction when overexpressed, but does not severely impair normal bleeding when under-expressed. Integrin... Problem: There is a need for new therapeutics that prevent cardiovascular diseases with minimal effects on normal blood clotting. Integrin α2β1 is a good therapeutic target since it can lead to cardiovascular diseases including stroke or myocardial infarction when overexpressed, but does not severely impair normal bleeding when under-expressed. Integrin α2β1 has been implicated in several other disease states including cancer metastasis, wound healing, viral infections (such as rotaviruses), and glomerular injury. Therefore, novel inhibitors of integrin α2β1 could have potential...
The technology presented is a breakthrough in the diagnosis of lymphatic filariasis, specifically targeting the B. malayi pathogen. It encompasses a novel soluble antigen extract used in both IgG and IgG4-based ELISA tests, aimed at detecting the presence of the filarial infection. This innovation serves as a cornerstone for a CLIA-certified reference test, established and utilized in Dr. Nutman's laboratory since the late 1980s. It offers a significant advancement in the field, particularly beneficial for remote areas where traditional PCR methods are challenging to implement, thereby facilitating more accessible point-of-care diagnostics for B. malayi infection. Commercial applications: The ELISA technology for B. malayi has vast potential applications including widespread field diagnostics in endemic regions, integration into routine health screenings, and use in epidemiological surveillance programs. It also holds promise for...
Summary: Scientists at the National Cancer Institute (NCI) have discovered a novel therapeutic, diagnostic and prognostic target for thrombosis: Soluble Tissue Factor (sTF). NCI has generated first-in-class antibodies and platform selectively neutralizing pathological coagulation while preserving normal hemostasis. This platform technology can be used to prevent, diagnose and treat pathological thrombosis caused by a variety of clinical conditions-including cancer, sepsis, infectious diseases (e.g., COVID), autoimmune disorders, trauma, heart conditions and inflammatory conditions. It offers a much more sensitive and specific test of thrombosis than the current D-dimer test. It may be applicable to any clinical condition which induces necroptosis, pyroptosis and NETosis, such as cancer, neurodegenerative disease, ischemia-reperfusion and acute injuries, traumatic injuries, bacterial and viral infections, cardiovascular conditions, and...
This invention pertains to nucleic acid-based assays for the detection of Aspergillus and other filamentous fungi. Assays cover the species-specific detection and diagnosis of infection by Aspergillus , Fusarium , Mucor , Penecillium , Rhizomucor , Absidia , Cunninghamella , Pseudallescheria or Sporthrix in a subject. This can reduce identification time from several days by conventional culture methods to a matter of hours. Furthermore, genus-specific probes are also provided for Aspergillus , Fusarium and Mucor , in addition to an "all-fungus" nucleic acid probe. This technology is readily adaptable as kits used for species-specific identification of opportunistic pathogen infections or possible work/home contamination. Commercial applications: Directing antifungal drug therapy for improved patient outcomes. Detection, discrimination of fungal species from biological samples. Addressing secondary infections of immunosuppressed...
Flaviviruses such as Zika virus, dengue virus, West Nile virus, yellow fever virus, and Japanese encephalitis virus cause widespread illness and death throughout the world. Typically, flaviviruses get transmitted through the bite of infected mosquitoes and ticks. CDC has identified and characterized distinct flavivirus cross-reactive epitopes (specific pieces of the antigen to which an antibody binds) that can improve serodiagnosis and vaccination against flaviviruses. CDC’s new flavivirus VLPs have structural proteins as the basis to form the viral particles. They do not have a viral genome so they are non-infectious. For the base, CDC researchers adapted human embryonic kidney 293 (HEK-293) cells, which are FDA-approved for use in producing biologics, in a serum-free and animal protein-free culture media, then propagated these as suspension cells. Researchers introduced an optimized plasmid to form the virus-like particles (VLPs) or...
A topically administered stapled peptide prevents Herpes Simplex Virus-1 DNA replication for improved treatment of Herpes Ocular Keratitis. Applications: Treatment of HK infections alone or in combination with ACV Treatment of additional ACV-resistant HSV-1 infections Prevention of HSV-1 propagation Inventors: Robert Ricciardi.
Stat 5a Knockout: Stat5a deficiency results in the loss of prolactin-dependent mammary gland development and lactogenesis. Prolactin induces mammary gland development and lactogenesis. Binding of Prolactin to its receptor leads to the phosphorylation and activation of STAT (signal transducers and activators of transcription) proteins. Two Stat proteins, Stat 5a and Stat5b, are expressed in mammary tissues during pregnancy. Stat5a null mice developed normally, and were indistinguishable from hemizygous and wild-type littermates in size, weight and fertility. Mammary lobulo-alveolar outgrowth during pregnancy was reduced and females failed to lactate after parturition. Stat5b, despite 96% similarity to Stat5a, could not compensate for the loss of Stat5a. Stat5a is the principal and obligate mediator of mammopoietic and lactogenic signaling. Commercial applications: Mouse model to study mammopoietic and lactogenic signaling. Source...
Conditional knockout of Stat5a and Stat5b: Combined deletion of conserved Stat5a and Stat5b in mammary epithelium at different times during pregnancy reveal multiple distinct functions. The signal transducer and activator of transcription (STAT) family of transcription factors conveys signals from membrane receptors to the nucleus, where they activate diverse genetic programs. Stat5a and Stat5b are highly conserved proteins that are activated by many cytokines, erythropoietin, prolactin and growth hormone. Despite their similarities, they have many unique functions. Stat5a deficiency results in the loss of prolactin-dependent mammary gland development, but does not affect body growth. Inactivation of Stat5b does not adversely affect mammary development and function, but leads to severe growth retardation. To study the effects of combined deficiency of Stat 5a and 5b before and during pregnancy, loxP was added to the ends of a DNA...
A human mast cell line LAD2 that more closely resembles normal in vivo and in vitro human mast cells by expressing functional FcepsilonRI receptors and responding to stem cell factor (SCF) with proliferation, as described in Leuk Res. 2003 Aug;27(8):677-82 and developed by the laboratory of Dr. Dean Metcalfe at the National Institute of Allergy and Infectious Diseases. This cell line also releases mediators by cross-linking FcgammaRI (CD64) receptors and express FcgammaRII (CD32). Commercial applications: A research material that can be used in the development of assays, validation of products or in quality control.. Competitive advantages: Speed up product development with NIH developed material that has already been tested and validated.. Source institute: NIAID. Inventors: Kirshenbaum, Arnold, Akin, Cem, Metcalfe, Dean.
Approaches and Design Techniques to Alleviate Coagulation-Related Acute Side Effects of Lung-Targeted Nanocarriers Problem: Lipid nanoparticles (LNPs) play a crucial role in drug delivery, enabling targeted drug administration to specific tissues. LNPs tailored for lung-specific delivery often incorporate cationic (positively charged) lipids. Unfortunately, this inclusion has resulted in adverse effects, including inflammation, lethargy, and internal lung tissue damage. These unresolved side effects currently render such lung-targeted LNPs unsuitable for human therapeutic use. Solution: Extensive mouse model testing in Dr. Brenner's lab has identified excessive coagulation occurs as a result of cationic LNP delivery and is the primary cause of these downstream acute side effects. Addressing this issue could involve several strategies: pre-treatment of patients with direct thrombin inhibitors such as Bivalirudin, limiting nanocarrier...
Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Unbalanced expression levels of ALDHs have been associated with a variety of disease states such as alcoholic liver disease, Parkinson’s disease, obesity, and multiple types of cancers. ALDH1A1 also plays a major role in preserving the tumor microenvironment via differentiation, self-protection, and proliferation of cancer stem cells. The cancer cell stemness is associated with cancer relapse and poor prognosis, raising the potential of ALDH1A1 as an attractive therapeutic target. We performed a systematic medicinal chemistry optimization and biological characterization of newly designed quinoline series that ultimately led to potent ALDH1A1 inhibitors with excellent enzymatic potency and Aldefluor cellular activity (e.g., MIA PaCa-2, OV-90, HT-29 cancer cell lines), as well as...
Summary: The National Eye Institute seeks research co-development partners and/or licensees for a STAT3 antibody that can suppress uveitis. Description of Technology: Uveitis is caused by inflammation in the eye that causes pain and reduce vision in affected patients. Rates of uveitis in the United States occurs 1 in every 200 people with eye-related irritation. Permanent damage, such as vision loss, occurs if uveitis goes untreated. Prolonged use of drugs that help treat chronic uveitis, such as periocular or intravitreal corticosteroid injections, can cause serious side-effects such as glaucoma. Therefore, finding alternative treatments for uveitis is an imperative. Signal transducers and activators of transcription-3 (STAT3) regulates the differentiation of pathogenic Th17 lymphocyte cells implicated in several autoimmune diseases. Genetically modified mice incapable of inducing Th17 cells are resistant to developing uveitis....
Summary: The National Cancer Institute (NCI) seeks research co-development partners and/or licensees to develop hetIL-15 in combination with other agents, such as PPARa agonists (Fenofibrate), FLT3 inhibitors (quizartinib), IL-12, or chemotherapy into a therapeutic for cancer. Description of Technology: Immunotherapy has emerged as a promising treatment strategy for many types of cancer. However, a major challenge is “exhausted” tumor-infiltrating immune cells, which lose their ability to effectively eliminate cancer cells. To address this issue, researchers are exploring ways to reverse immune exhaustion and improve treatment outcomes. One potential approach involves interleukin-15 (IL-15), a cytokine that promotes the growth and killing ability of tumor-specific CD8+ T cells and NK cells. IL-15, either alone or in combination with other agents, has shown some promise in clinical trials. However, its use is hindered by toxicity at...
Summary: The NCI seeks co-development partners or licensees to further develop the novel ExoVII inhibitor(s) as antibiotic adjuvants for enhancing the efficacy of quinolone antibiotics, particularly in quinolone-resistant bacterial strains. Description of Technology: Topoisomerase poisons, such as quinolone antibiotics, are widely used as anticancer drugs and antibiotics. Quinolone antibiotics act by trapping prokaryotic type IIA topoisomerases (DNA gyrase and TOPO IV), resulting in irreversible topoisomerase cleavage complexes. However, current U.S. Food and Drug Administration (FDA) guidance reserves the use of quinolones for the most serious bacterial infections due to their associated side effects and to limit the occurrence of drug-resistant bacterial strains. Resistance to available antibiotics in pathogenic bacteria is a global challenge as the number of drug-resistant strains increased dramatically each year. Combination of...
Existing microsphere technologies are used as therapy for certain cancers. The therapy is by way of occlusion, when the microspheres are delivered into blood vessels that feed a tumor. The physical dimensions of the microspheres occlude the blood supply and thus, killing the tumor. Some microspheres have also been modified to bind protein, elute drugs, and reduce inflammatory reactions as part of the therapy. However, one technical short-coming of existing microsphere technology is a limited capability to be visualized in real-time. The inability to visualize embolic microspheres during treatment and post treatment could lead to complications and the need for additional treatments, thereby increasing the chance of additional complications. Researchers at the National Institutes of Health – Clinical Center (NIH-CC) have developed a technology that uses bismuth-based beads with a hydrophilic polymer to allow for real-time tracking with...
This technology includes synthesis of S-2-((S)-3-(4-chlorophenyl)-N'-((4-chlorophenyl) sulfonyl)-4-phenyl-4,5-dihydro-1 H-pyrazole-1-carboximidamido)- 3-(methyld3) butanamide-d5, octadeuterated JD5037 for possible use in clinical Absorption, Distribution, Metabolism, and Excretion (ADME) studies for drug discovery studies. Commercial applications: Use in ADME studies for drug discovery. Competitive advantages: Novel; first synthesis of d8-JD5037. Source institute: NIAAA. Inventors: Iyer, Malliga, Cinar, Resat, Coffey, Nathan.
Peptides derived from the human apolipoprotein B that are antimicrobial, anti-inflammatory, highly cytotoxic, and do not select for bacterial resistance. Problem: In 2019, more than 2.8 million people in the U.S. suffered from antibiotic-resistant infections, leading to over 35,000 deaths. Such infections are of great concern, especially for ESKAPE pathogens, which have growing resistance to commonly used antibiotics. It has been estimated that 10 million people would die each year from these untreatable diseases by the year 2050 at the present rate. Therefore, there is an urgent need to develop alternatives to conventional antibiotics to treat drug-resistant infections. Solution: Four encrypted peptides that have been derived from human apolipoprotein B exhibit antimicrobial, anti-inflammatory, and highly cytotoxic properties. When combined, the peptides potentiated the activity of conventional antibiotics against bacteria and do not...
It is well known that overactive Ras signaling is linked to many forms of cancer, and despite intensive efforts worldwide to develop effective inhibitors of Ras, to date there is no anti-Ras inhibitor in clinical use. Researchers at the NCI’s Cancer and Inflammation Program , in collaboration with scientists at Vanderbilt University and the University of Illinois in Chicago, have identified a number of small peptidomimetic compounds that bind to Ras proteins with nanomolar affinity. The development of compounds was based on two previously unknown mechanisms of Ras regulation uncovered due collaborative efforts of the three groups. The researchers have found that hypervariable regions (HVR) of some isoforms of Ras proteins function as negative regulators of Ras activity. Rational design lead to generation of metabolically stable cell-permeable analogs of HVRs with much improved binding affinity and anti-tumor activity. The second class...
Description of Technology: CD22 is a protein expressed by normal B cells and B-lymphoid malignancies. Its limited tissue expression pattern makes it a safe antigen for targeted therapies, such as T-cell Receptor (TCR)-T cell therapy. CD22-targeting therapies already on the market, mainly antibody-immunotoxin conjugates and chimeric antigen receptors (CAR)-T cells, have limitations such as resistance to treatment and/or side effects. Resistance mechanisms to the current CD22 therapies involve loss or modulation of target antigen on the cell surface. TCRs are expected to overcome these resistance mechanisms as they use distinct target recognition mechanism. TCRs instead recognize epitopes derived from proteins processed intracellularly and presented in the context of Human Leukocyte Antigens (HLA), enabling detection of broad antigens inaccessible to antibodies or CAR-T’s – including neoantigens, cancer germline antigens, and...
Summary: The NCI seeks parties interested in research co-development and/or licensing of these HLA-A*0301 restricted TCRs that target the BRAF V600E mutation. Description of Technology: BRAF is an oncogene that encodinges a serine-threonine kinase (B-Raf kinase) important in regulating cell growth and differentiation. Spontaneous mutations in the BRAF gene allow cells to continuously divide, leading to the development of cancer. A substitution of glutamic acid for valine at amino acid number 600 (designated V600E) accounts for 90% of BRAF mutations and is a driver of many cancers. The V600E mutation is present in ~3% of all cancer cases, representing a patient population of 540,000 patients per year. Though While the V600E mutation is found in a wide variety of cancers, it ishas a particularly high prevalentce in metastatic melanoma, colorectal cancer, thyroid cancer, and lung cancer. Many of these cancers are aggressive and the V600E...
Summary: The NCI seeks parties interested in research co-development and/or licensing this library of TCRs targeting CDKN2A mutations. Description of Technology: Cyclin-dependent kinase inhibitor 2A gene, also known as CDKN2A, is a tumor suppressor gene and is commonly inactivated through somatic mutations in many human cancers. For example, inactivation of CDKN2A is highly prevalent in melanoma, gastrointestinal and pancreatic cancers. Through germline mutations, CDKN2A is associated with predisposition for a variety of cancers, including melanoma and pancreatic cancers. Despite the high frequency of CDKN2A mutations in cancer, there have been no successful therapies targeting these mutations to date. Adoptive cell therapy, a promising form of immunotherapy, offers a potential form of targeted therapy for cancers with CDKN2A mutations. Researchers at the National Cancer Institute (NCI) have developed seven novel human T cell...
Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors. Point mutations in the KRAS gene most frequently affect amino acid position 12, resulting in the substitution of the native glycine (G) residue for other amino acids (e.g., aspartic acid (D), valine (V), cysteine (C) or arginine (R)). The mutations in KRAS occur early in the process of carcinogenesis, and only tumor cells express driver mutations, making them an attractive cancer-specific therapeutic target. However, despite decades of research into the signaling of mutated KRAS and druggability of these mutations with selective inhibitors, no effective therapy has been developed for these common mutated KRAS-driven cancers. T cell receptors (TCRs) are proteins expressed on the cell surface of T lymphocytes that can recognize peptide antigens from infected...
The tumor protein p53 is a cell cycle regulator. It responds to DNA damage by triggering the DNA repair pathway and allowing cell division to occur or inducing cell growth arrest, cellular senescence, and/or apoptosis. p53 therefore acts as a tumor suppressor by preventing uncontrolled cell division. However, mutations in p53 that impair its cell cycle regulatory functions can induce uncontrolled cell division leading to cancer. Certain p53 mutations, termed ‘hotspot’ mutations, occur at high frequency across patients and diverse cancer types, such as cholangiocarcinoma, melanoma, colon cancer, rectal cancer, ovarian cancer, endometrial cancer, non-small cell lung cancer (NSCLC), glioblastoma, uterine cervical cancer, head and neck cancers, breast cancer, pancreatic cancer, and bladder cancer. Novel therapeutics that specifically target mutant p53 proteins may be useful for the treatment of many common malignancies. Researchers at the...
Available for licensing are methods to generate T cells responsive to multiple polyomaviruses. The resulting T cell populations could be useful in treating immunosuppressed individuals with polyomavirus infections or polyomavirus-associated pathologies such as Merkel cell carcinoma (MCC), polyomavirus-associated nephropathy (PVAN), hemorrhagic cystitis, progressive multifocal leukoencephalopathy (PML), and trichodysplasia spinulosa (TS). The methods could also be used to restore polyomavirus-specific immunity in immunocompromised individuals. Commercial applications: Immunotherapy for immunosuppressed individuals with polyomavirus-associated pathologies.. Competitive advantages: Methods allow development of polyomavirus antigen-specific T cells.. Source institute: NHLBI. Inventors: Chinnasamy, Dhanalakshmi, Muranski, Pawel, Buck, Christopher, Barrett, John.
Antigen-specific immunotherapy with engineered cytotoxic T cells targeting misformed proteins to treat neurodegenerative and muscular diseases. Problem: Neurodegenerative and muscular diseases, such as amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM), and Alzheimer’s disease (AD), collectively affect over 5 million adults in the United States. Patients with these diseases suffer from progressive muscle weakening and/or neuron degeneration, which often leads to death; despite extensive research, no effective treatments currently exist. Scientific evidence suggests that antigen-specific T cells may play a role in these diseases, but the development of antigen-specific therapies have been limited by the lack of understanding in the antigen and T cell receptor (TCR) pairs that drive these diseases and difficulties in identifying antigen targets. Solution: In many ALS, IBM, and AD patients, abnormal buildup and...
Epidermal growth factor receptor (EGFR) is a transmembrane protein involved in cell growth and proliferation. Mutations in this protein can lead to overexpression, causing several types of cancer; notably, non-small cell lung cancer (NSCLC). For example, mutations in EGFR are found in up to 50% of NSCLC patients and the E746-A750 deletion accounts for 30-40% of such EGFR mutations. Currently, there are no available therapeutics that specifically target the E746-A750 deletion. Researchers at the National Cancer Institute (NCI) have isolated T cells that recognize the EGFR E746-A750 deletion. Retroviral transfer of the TCR genes conferred recognition of tumor cell lines with EGFR E746-A750 deletion in the context of HLA DPA1*02:01 and DPB1*01:01. These HLAs exists in about 10% of Caucasians and 50% African Americans, respectively, in the US. This discovery allows for the specific elimination of tumor cells with E746-A750 deletion...
Metastatic cancers cause up to 90% of cancer deaths, yet few treatment options exist for patients with metastatic disease. Adoptive transfer of T cells that express tumor-reactive T-cell receptors (TCRs) has been shown to mediate regression of metastatic cancers in some patients. Unfortunately, identification of antigens expressed solely by cancer cells and not normal tissues has been a major challenge for the development of T-cell based immunotherapies. Thus, it is essential to find novel target antigens differentially expressed in cancer versus normal tissues. Inventors at the National Cancer Institute (NCI) have developed a TCR that specifically targets the Kita-Kyushu Lung Cancer Antigen 1 (KK-LC-1) 52-60 epitope. KK-LC-1 antigen (encoded by the CT83 gene) is highly expressed by several common and aggressive epithelial tumor types. Importantly, KK-LC-1 is expressed at very low levels in normal tissues and not in those tissues...
Human cancers contain genetic mutations that are unique to each patient. Some of the mutated peptides are immunogenic, can be recognized by T cells, and therefore, may serve as therapeutic targets. Scientists at the National Cancer Institute's Surgery Branch developed a method to identify T cells that specifically recognize immunogenic mutations expressed only by cancer cells. The scientists identified cancer-specific mutations from a patient with widely metastatic cholangiocarcinoma by sequencing tumor samples and comparing with normal cells. Using tandem minigene constructs encoding all of the mutations expressed by a patient's tumor, the inventors identified T cells that recognized the immunogenic mutations from the same patient. These mutation-reactive T cells have the potential to eliminate the cancer cells while sparing normal tissues since normal tissues do not express the mutations. The mutation-reactive T cells were expanded...
Description of Technology: Human cancers contain genetic mutations that are unique to each patient. Some of the mutated peptides are immunogenic, can be recognized by T cells, and therefore, may serve as therapeutic targets. Scientists at the National Cancer Institute's Surgery Branch developed a method to identify T cells that specifically recognize immunogenic mutations expressed only by cancer cells. The scientists identified cancer-specific mutations from a patient with widely metastatic cholangiocarcinoma by sequencing tumor samples and comparing with normal cells. Using tandem minigene constructs encoding all of the mutations expressed by a patient's tumor, the inventors identified T cells that recognized the immunogenic mutations from the same patient. These mutation-reactive T cells have the potential to eliminate the cancer cells while sparing normal tissues since normal tissues do not express the mutations. The...
A method to streamline the process of generating chimeric antigen receptor (CAR) T cells for therapeutic applications. Problem: CAR T cell therapy has demonstrated clinical success in treating various forms of cancer. With more CAR T cell therapies projected to gain regulatory approval, manufacturing becomes increasingly important in the face of this rising demand. Currently, engineering of CAR T cells ex vivo is a lengthy and complicated process that involves leukapheresis, artificial T cell activation, and CAR construct delivery. In particular, artificial T cell activation generally employs magnetic beads (Dynabeads®) conjugated with CD3 and CD28 antibodies to mimic the natural process mediated by antigen presenting cells (APCs). While effective, a downside of this method is the need to remove the magnetic beads prior to clinical administration of the cell product. This cumbersome process can hamper cell yields and augment...
Summary: The NCI seeks applications from parties interested in co-developing and/or licensing a method to develop improved cancer immunotherapies. Description of Technology: Adoptive T-cell therapy (ACT) utilizes tumor-reactive T cells to induce disease remission. While ACT has been used effectively to treat metastatic melanoma and certain epithelial cancers, most patients do not respond to treatment. Although the mechanisms underlying this variable response to therapy are not fully elucidated, the phenotype of the adoptively transferred cell is known to be a key determinant of treatment efficacy. Researchers at National Cancer Institute’s (NCI) Surgery Branch have now determined that the CD3 + CD39 - CD69 - subpopulation of T cells are highly associated with complete disease response following ACT. Leveraging over 30 years of ACT clinical data and associated biological materials, NCI researchers immune-profiled archived infusion...
Summary: The NCI Center for Immuno-Oncology is actively seeking co-development partners and/or licensees for this E6-targeting TCR with therapeutic potential for HPV-positive conditions. Description of Technology: Human papillomavirus (HPV) is a group of human viruses known to cause various malignancies. Of the group, HPV-16 is the most prevalent strain – an estimated 90% of adults have been exposed. HPV-16 is also the strain most commonly associated with malignancy, causing the vast majority of cervical, anal, vaginal, vulvar, and penile cancers. Currently, HPV-positive malignancies non-responsive to surgery or radiation are incurable and poorly palliated by existing systemic therapies. Thus, an alternative therapeutic approach for HPV-positive malignancies is needed. Researchers at the National Cancer Institute (NCI) developed a T cell receptor (TCR) that may be used in adoptive cell therapy to treat HPV-positive malignancies. The...
Summary: The NCI Center for Immuno-Oncology is actively seeking co-development partners and/or licensees for this E7-targeting TCR with therapeutic potential for HPV-positive conditions. Description of Technology: Human papillomavirus (HPV) is a group of human viruses known to cause various malignancies. Of the group, HPV-16 is the most prevalent strain – an estimated 90% of adults have been exposed. HPV-16 is also the strain most commonly associated with malignancy, causing the vast majority of cervical, anal, vaginal, vulvar, and penile cancers. Currently, HPV-positive malignancies non-responsive to surgery or radiation are incurable and poorly palliated by existing systemic therapies. Thus, an alternative therapeutic approach for HPV-positive malignancies is needed. Researchers at the National Cancer Institute (NCI) developed a T cell receptor (TCR) that may be used in adoptive cell therapy to treat HPV-positive malignancies. The...
Summary: NCI seeks parties interested in licensing to further develop a collection of novel anti-CD20 TCRs that can be used to treat CD20 positive lymphomas and leukemias. Description of Technology: CD20 is a protein expressed by wide ranges of lymphoid malignancies originating from B cells but not by indispensable normal tissues, making it an attractive target for therapies such as T-cell receptor (TCR) therapy. Current anti-CD20 therapeutics face a number of limitations. The most important limitation to current anti-CD20 therapies include cancer cells becoming resistant to the therapy. Resistance mechanisms to the existing CD20 therapies include loss of target antigen expression from the cell surface, loss of antibody epitope, or modulation of antibody epitope – all of which make the malignant cells “invisible” to antibodies. Importantly, these resistance mechanisms do not affect TCR-mediated target recognition. Epitopes for TCRs...
In order to develop a simple detection assay for field use, CDC researchers cloned and sequenced the Taenia solium T24 diagnostic protein. The T24 sequences can be used to detect and diagnose T. solium infection or can be formulated into a pharmaceutical composition. T. solium is a species of tapeworm. Intestinal infection with T. solium is referred to as taeniasis. Many taeniasis infections are asymptomatic but may be characterized by insomnia, anorexia, abdominal pain and weight loss. Cysticercosis infection, which can be fatal, may develop if T. solium larvae migrate out of the intestine and form cysticerci in various body tissues. This technology may be used to develop a diagnostic, vaccine, or therapeutic for infection related to T. solium . Commercial applications: Vaccine or therapeutic for taeniasis or cysticercosis resulting from T. solium infection. Diagnosis of T. solium infection. Zoonotic disease research and...
Inhibitors of TIP60, maintaining regulatory T cells (Tregs) and ameliorating autoimmune diseases. Problem: Inflammatory bowel disease (IBD) involves chronic inflammation of all or part of digestive tract. IBD includes ulcerative colitis and Crohn’s disease both very prevalent and known to cause severe complications and discomfort. Inhibitors of TIP60, a histone acetyltransferase, have been developed to maintain peripheral Treg cells, further enabling them to ameliorate autoimmune diseases. Preliminary animal studies have focused on the treatment of colitis, but these compounds are expected to find application in a wide variety of autoimmune disorders. Solution: Dr. Greene’s laboratory synthesized small molecules that bind and modulate TIP60 acetyltransferase activity. Lead compounds tested bind to TIP60’s non-active site while maintaining its scaffolding ability. As a result, TIP60 binds FOXP3 and recruits p300, leading to FOXP3’s...
Hearing loss is a common communication disorder affecting nearly 1 in 1,000 children in the United States alone, and nearly 50% of adults by the age of eighty. Hearing loss can be caused by environmental and disease-related factors; however, hearing loss due to genetic factors accounts for approximately 50% of cases. The NIH announces the isolation of two novel genes involved in hearing; TMC1, short for transmembrane channel-like gene 1. The inventors have discovered that dominant and recessive mutations in TMC1 underlie two forms of hereditary deafness, known as DFNA36 and DFNB7/11. TMC1 encodes a protein required for normal function of the mammalian hair cell, which plays a critical role within the hearing pathway that detects sound in the inner ear. The invention discloses TMC1 nucleic acids, vectors, and cells. Also disclosed are methods of detecting hearing loss, or a predisposition to hearing loss, due to a mutation in TMC1, as...
Tumor Necrosis Factor (TNF) is a potent pro-inflammatory cytokine whose dysregulation has been found to cause rheumatoid arthritis, stroke and a broad range of inflammatory disease. Inhibition of TNF receptors has become an effective means to ameliorate inflammatory disease, however, pan TNF-R antagonists increase risk of infection and malignancy. Using a novel structure based design approach to identify small molecule compounds that bind to an allosteric site on TNF-R1, thus inhibiting binding of TNF-alpha to TNF-R1 and reducing activation of the TNF-alpha/TNF-R1 signaling pathway, the inventors have uncovered a new class of compounds that are effective at inhibiting the pathologic side-effects of TNF signaling while preserving the patient's ability to mount an immune response against pathogens. Lead candidates are potent, highly specific and have been demonstrated to ameliorate arthritis in vivo. Inventors: Mark Greene.
TRPCs (Canonical Transient Receptor Potential Channels) are a group of non-selective cation channels that allow sodium and calcium into cells. There are seven different genes in mice that code TRPCs. The in vivo roles played by TRPCs as a whole are poorly understood and very little is known about the in vivo roles played by individual TRPCs nor the role of these channels in specific tissues or cells. In this invention, mice with a floxed allele of TRPC3, TRPC5, or TRPC7 were generated. Knockout mice of TRPC3, TRPC5, or TRPC7 can be used to study the function of the respective genes. The knockout mice can then be used to identify TRPC3/TRPC5/TRPC7-dependent processes. When mice with a floxed allele of one of the TRPCs are crossed with mice expressing Cre recombinase, mice can be generated in which TRPC3 has been deleted. This can be done in a tissue specific manner. Commercial applications: This mouse model could be used to identify...
The disclosed invention provides materials and methods to treat granulocytopenia (low white cell count in the blood) which is characterized by a reduced number of granulocytes (relative) or an absence of granulocytes (absolute). This condition is commonly associated with cancer chemotherapy, but is seen less frequently in a number of conditions including the use of propylthiouracil, radiotherapy for marrow ablation for bone marrow transplantation, aplastic anemia, systemic lupus erythematosus, AIDS and a variety of other situations. The invention proposes a method to increase GM-CSF levels in a treated subject, and this increase is achieved by inhibiting the degradation of GM-CSF messenger RNA (mRNA). Tristetraprolin (TTP) is one member of a family of cys-cys-cys-his (CCCH) zinc finger proteins, and it is a factor that binds to and causes the instability of GM-CSF mRNA. Methods are provided for the development of screening assays for...
Summary: The National Eye Institute seeks research co-development partners and/or licensees for an adeno-associated viral gene therapy for Oculocutaneous Albinism type 1A. Description of Technology: Oculocutaneous albinism (OCA) is a genetically heterogeneous congenital disorder characterized by decreased or absent pigmentation in the hair, skin and eyes. The absence of pigmentation is caused by insufficient melanin production – an important pigment providing normal black color to important eye tissues such as the iris and retinal pigment epithelium. Lack of melanin in the eye results in abnormal development and impaired vision. Individuals diagnosed with OCA1, the most common type if albinism worldwide (1:40,000 people), is caused by mutations in the TYROSINASE (TYR) gene. OCA1A patients suffer complete loss of melanin caused by inactivity of the TYROSINASE enzyme. Currently, there is no treatment. Scientist at the National Eye...
Problem: Pulmonary arterial hypertension (PAH) is a severe lung disease characterized by elevated pulmonary arterial pressure that is estimated to affect 5,000-15,000 people in the US. Without proper treatment, the elevated pressure leads to heart failure and eventually death—median survival without treatment is around 2-3 years. Management and... Problem: Pulmonary arterial hypertension (PAH) is a severe lung disease characterized by elevated pulmonary arterial pressure that is estimated to affect 5,000-15,000 people in the US. Without proper treatment, the elevated pressure leads to heart failure and eventually death—median survival without treatment is around 2-3 years. Management and treatment of PAH may help slow down disease progression, but the mortality rate in patients with intermediate- to high-risk (approximately 88% of patient population) remains high. Solution: Molecular profiling and clinical studies have identified the...
A method to inhibit small extracellular vesicles (sEVs) released by tumor cells to enhance lipid nanoparticle (LNP) accumulation in tumors. Problem: Lipid nanoparticles (LNPs) have shown promise as drug delivery systems for various diseases with several clinically approved products. However, their ability to deliver genes specifically to tumor cells has been limited and challenging. This results in reduced nanoparticle penetration and accumulation within tumors, ultimately lowering the treatment’s effectiveness. Therefore, there is a need to improve delivery efficiency to enhance the treatment outcome. Solution: The inventors found that sEVs from tumor cells function as barriers by binding to LNPs and directing them to the liver, reducing tumor accumulation. Inhibiting the Rab27a gene, which controls sEV secretion, enhances nanoparticle delivery. Co-delivering LNPs with small interfering RNA (siRNA) targeting Rab27a decreases sEV...
Targeted therapies that specifically modulate epithelial and hair follicle–driven inflammation in hidradenitis suppurativa and related hair disorders without broad systemic immunosuppression.
The National Cancer Institute's Urologic Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of Tempol to target HIF-2a in cancer. Elevated HIF-2a is associated with clear cell kidney cancer characterized by mutation of the VHL tumor suppressor gene and with many other cancers. A commercially-available stable nitroxide, TEMPOL, can effectively reduce the level of hypoxia-inducible transcription factor (HIF)-2a. Therefore, TEMPOL can potentially be developed into a cancer drug to treat patients with elevated HIF-2a, whether due to compromised VHL function or not. The potential drug could target a population that suffers from genetic diseases such as inherited von Hippel-Lindau (VHL) disease and patients with kidney and other cancers characterized by elevation of HIF-2a. Inherited VHL disease is a cancer syndrome caused...
Interleukin-15 (IL-15) and IL-21 have been reported to support the function of anti-tumor T cells. However, their use in the clinic has been constrained, in part, by dose-limiting toxicity and the need for repeated administration. To overcome these limitations, researchers in the National Cancer Institute (NCI) Experimental Transplantation and Immunology Branch (ETIB) have developed synthetic IL-15 and IL-21 molecules for autocrine expression by the engineered therapeutic T cells. These molecules were designed with flexible linkers that connect to cell membrane anchors. This, in turn, reduces systemic toxicity caused by free cytokine molecules. The inventors have shown that co-expression of the novel IL-15 and IL-21 tethered molecules improves the anti-tumor efficacy of the therapeutic engineered T cells in vivo. Competitive Advantages: T cells that co-express the tethered IL-15 and IL-21 on their cell membrane can increase...
Thalidomide and its close analogs (lenalidomide and pomalidomide) are widely used to treat a variety of diseases, such as multiple myeloma and other cancers as well as the symptoms of several inflammatory disorders. However, thalidomide is known for its teratogenic adverse effects when first clinically introduced in the 1950s, and is associated with drowsiness and peripheral neuropathy. Hence, there is intense interest to synthesize, identify and develop safer analogs. Researchers at the National Cancer Institute n synthesized novel thalidomide analogs that demonstrate clinical potential without being teratogenic, as initially evaluated in in vivo zebrafish and chicken embryo model systems and in cell culture. These new compounds differentially provide potent anti-angiogenesis and/or anti-inflammatory action. The agents have potential for development of new cancer therapies and treatment of a number of neurological and systemic...
CDC researchers have developed probes and primers for detecting the 2009 pandemic influenza A H1N1 virus in patient samples using real-time reverse transcription-polymerase chain reaction (rRT-PCR) methods. These primers and probes were originally developed in 2009 and were cleared by the FDA as part of a domestic human diagnostic testing panel in June 2010. These were also updated to increase specificity and/or sensitivity of the detection methods. The compositions and methods can be used to quickly identify 2009 pandemic influenza A (pdm InfA) and pandemic H1 (pdm H1), other influenza A virus sub-types (e.g., H3, H5, H7, and H9) and influenza B virus sub-types present in a sample. The CDC-developed probes and primers permit the rapid detection and/or discrimination of influenza virus subtype nucleic acids in initial clinical sample testing. Commercial applications: Influenza A & pandemic influenza diagnostics using clinical...
The base editing of phenylalanine hydroxylase enzyme in the liver to restore phenylalanine metabolism and prevent neurotoxic effects. Problem: Phenylketonuria (PKU) is a severe disorder affecting approximately 1 in 10,000 U.S. newborns. PKU is marked by a genetic mutation in the phenylalanine hydroxylase enzyme (PAH), resulting in phenylalanine (Phe) buildup. Early detection and management through strict dietary Phe restriction can prevent severe intellectual disability. Additional treatments include large neutral amino acids and glycomacropeptide supplementation, though with limited success. Finally, there are the FDA-approved adjuvant treatment for PKU, sapropterin dihydrochloride, and the enzyme substitution therapy pegvaliase, which also have limited efficacy. Owing to the restricted therapeutic modalities for PKU, novel approaches are required to fill this unmet need. Solution: This invention offers a genetic engineering approach...
Cancer is the second leading cause of death worldwide. The primary cause of mortality from cancer is metastasis. While the underlying mechanisms of cancer metastasis are still being unraveled, the gp78 protein involved in ER-associated degradation (ERAD) appears to play a role in metastasis in sarcoma. Targeting gp78 may be a therapeutic option in cancer treatment. The prometastatic activity of ERAD requires the E3 ubiquitin ligase activity of gp78. Gp78 targets the transmembrane metastasis suppressor, KAI1, for degradation. Suppression of gp78 results in the accumulation of KAI1 and a reduced metastatic potency of sarcoma cells. Regulating gp78 presents a new therapeutic strategy for the treatment of sarcomas. The National Cancer Institute (NCI) is seeking statements of capability or interest from parties interested in licensing or in collaborative research to co-develop technologies that disrupt gp78 activity and/or ERAD activity...
Biological materials are important research tools that can be used for diagnostic as well as therapeutic purposes. Antibodies have become viable drugs in the market today and there is a general market need for systems that may facilitate production of efficient and effective antibodies. In recent years, monoclonal antibodies have gained significant importance in their use, both as diagnostics and therapeutics, to intervene and combat diseases such as cancer, cardiovascular diseases, and infections. The present invention relates to the discovery of rabbits, genetically defined as b9, as the biological vehicle for the isolation of chimeric phage displaying Fab with human constant regions and rabbit immunoglobulin heavy and light chain variable regions for the development of diagnostic antibodies and humanized monoclonal therapeutic antibodies of high affinity and specificity (Popkov et al., J. Molec. Biol. 325: 325-335, 2003; Popkov et...
This application describes a composition and method for treating inflammatory bowel disease or other autoimmune diseases. The composition utilizes a vector which contains a first promoter which controls the expression of a regulatory transcription factor and a second inducible promoter which controls the expression of the gene of interest. The preferred gene of interest encodes an isoform of TGF-beta such as TGF-beta 1 or TGF-beta 3 . The isoform of TGF-beta does not have to be hTGF-beta and can be a latent or active isoform of TGF-beta. The preferred inducible promoter is TRE-CMV which can be induced using doxycycline. The usefulness of the composition for treating autoimmune diseases is demonstrated in the application in a murine model of inflammatory bowel disease in which intestinal inflammation was abrogated by the administration of a plasmid vector encoding active TGF-beta. The composition may be administered by a variety of...
Diagnostic software to stratify patients on biomarkers and therapeutic targets. Problem: Targeted therapy has revolutionized the treatment of cancer. The efficacy of such therapy is highly dependent on target levels that may increase, decrease, or remain unchanged in the tumor compared to healthy tissue. In clinical practice, the target’s status may be tested through methods such as immunohistochemistry (IHC), which relies on a trained professional to group samples using an arbitrary cutoff. Such a semi-quantitative approach may lead to over-/under- estimation of the target expression and ineffective health interventions. Molecular assays can measure multiple biomarkers but lag in multiclass diagnostic capabilities. Solution: The inventor developed an original software that uses tissue biomarkers and rigorous statistical analysis to classify patients by target expression with speed and precision. Inventors: Marina Guvakova.
Two novel monoclonal antibodies were discovered that target pathological conformations of the tau protein. The antibodies were shown in vitro and in vivo to inhibit the spread of pathological tau protein aggregates, which is one of the defining characteristics of AD. Problem: More than 5 million Americans are living with Alzheimer’s disease which is the 6th leading cause of death ( Alzheimer’s Association. 2020 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement 2020 ). Current treatments do not adequately slow the progression of the diseases. By 2022, the market for AD therapeutics is expected to reach nearly USD $9 billion, a significant percentage of which is anticipated to be novel antibodies directed against tau, and beta amyloid proteins ( Potential Pipeline Disruptors, Kalorama Information, 2017 ). Intracellular tau protein aggregates are a pathological hallmark of AD. In the disease state, misfolded tau spreads from cell...
Immune checkpoint inhibitors (e.g. CTLA-4, PD-L1) have recently shown significant promise in the treatment of cancer. However, when used alone, these checkpoint inhibitors are limited by the absence or repression of immune cells within the targeted cancer. For those cancers associated with these limited immune systems, there remains a need for effective therapies. Agents capable of recruiting and activating immune cells to these types of cancers could extend the overall and complete response rates of combination therapies within the immunooncology domain. Researchers at the National Cancer Institute (NCI) have developed a combination therapy capable of recruiting and activating immune cells for the treatment of cancer. This therapy incorporates, HMGN1, an alarmin, which recruits immune cells using its chemotactic-induction capabilities, and activates dendritic cell maturation via its TLR4 agonism. The combination of HMGN1 with TLR7/8...
The only currently available treatment for Menkes disease, subcutaneous copper histidinate injections, is successful only in patients with ATP7A gene mutations that do not completely corrupt ATP7A copper transport function (estimated 20-25% of affected patients) and when started at a very early age (first month of life). The combination of viral gene therapy with copper injections provides working copies of the ATP7A copper transporter into the brain, together with a source of the substrate (copper) needed for proper brain growth and clinical neurodevelopment. Codon-optimized nucleic acids encoding a reduced-size ATP7A protein and compositions of AAV vectors were discovered by NICHD researchers along with methods of administering this therapy. Human P-type ATPase copper-transporting ATPase 1 (ATP7A) transports copper from enterocytes (where it is taken up from dietary copper) into the blood. ATP7A also mediates passage of copper...
The technology offered for licensing is in the field of Therapeutics. More specifically, the technology relates to biological ligands and their use as modulators of the production of Interferon gamma as a means to treat a broad spectrum of diseases. The invention describes and claims antibodies and other ligands that can stimulate Natural Killer (NK) immune cells to produce Interferon gamma which contributes to the combat against foreign pathogens. Conversely, the invention also describes and claims methods that can inhibit such Interferon gamma production for treatment of diseases where excess of Interferon is not desirable. The invention also describes methods and assays to identify both inducing and inhibiting ligands The license agreement may include biological materials, such as monoclonal antibodies that were made and identified by the inventors as Interferon gamma stimulators. Interferon-gamma is a potent antiviral and...
Interdependence of oncogenic and epigenetic mechanisms in T-cell lymphoma. Applications: Immuno-onco-therapeutic targets in lymphoma and other types of cancer Research tool to study cell transformation including its very early stages and to screen for compounds that could be effective in treating anaplastic large-cell lymphomas (ALCL) Research tool to generate immortalized, although abnormal, T lymphocytes from both, healthy individuals and patients with autoimmune and other diseases. Inventors: Mariusz Wasik.
Respiratory Syncytial Virus (RSV) infects nearly all children by their second birthday. RSV usually causes mild respiratory illness, however, a subset of patients experience severe infection that require hospitalization. Successful host defense against viral pathogens requires rapid recognition of the virus and activation of both innate and adaptive immunity. Toll-Like Receptors (TLRs) are responsible for mounting an innate immune response and genetic variations within TLRs modulate severity of infection. Researchers at NIEHS have identified a single nucleotide polymorphism (SNP) in TLR8 that is associated with RSV disease severity. The SNP is p53-responsive allele, indicating that p53, a master cell cycle regulator, can strongly influence TLR8 mediated immune responses. Identification of this SNP can inform diagnosis and prognosis of RSV disease and serve as a therapeutic target for severe RSV infection. Commercial applications:...
The glycoprotein CD56, also known as a neural cell adhesion molecule (NCAM), plays an important role in normal physiological functions. It is expressed in low levels in normal cells such as neurons, glia, skeletal muscle and natural killer cells. It is highly expressed on a variety of cancerous cells including those of neuroblastoma, small-cell lung cancer, and multiple myeloma. In neuroblastoma, patients undergo a very aggressive standard of care regimen that results in a high mortality rate. Many neuroblastomas have increased expression of CD56, which represents a possible therapeutic target for these aggressive and hard to treat cancers. Researchers at the National Cancer Institute's Cancer and Inflammation Program , in collaboration with the Children’s Hospital of Philadelphia (CHOP), have developed antibody-drug conjugates (ADC) that incorporate one of two novel human CD56 antibodies, known as m900 and m906, in combination with a...
Technology Overview: Duchenne Muscular Dystrophy (DMD) is the most common X-linked fatal neuromuscular disorder, affecting approximately 1 in every 3500 male births. It is characterized by progressive degeneration of skeletal and cardiac muscle due to a defective form of the gene dystrophin. There is currently no cure for DMD and the available treatment... Applications: Treatment of DMD Inventors: Tejvir Khurana.
Obesity is associated with buildup of fat within the cells of the liver, heart, and skeletal muscle. Intracellular fat accumulation leads to impairment in the ability of these cells to absorb glucose from the blood in response to insulin, called insulin resistance. However, the linkage between intracellular fat accumulation and insulin resistance is poorly understood. This invention has defined the upstream connection between fat accumulation in muscle cells and insulin resistance defining a new candidate target strategy for the treatment of obesity-related metabolic disorders. Applications: Treatment of obesity-related metabolic disorders Treatment for insulin resistance (type 2 diabetes) Inventors: Byungyong Ahn, Daniel Kelly, Teresa Leone, Satyamaheshwar Peddibhotla.
Neonatal brains are at high risk for seizures due to heightened electrical activity corresponding to neural development. Though anticonvulsant drugs exist to treat the seizures immediately, certain synaptic receptors (CP-AMPARs) become highly expressed, increasing the likelihood of developing epilepsy and autism-spectrum disorders. The inventors propose using CP-AMPAR blockers such as IEM-1460 to curb CP-AMPAR activity and prevent development of epilepsy and other neurological disorders. Problem: Neonatal brains are constantly in a state of electrical excitation due to the heightened neural activity required during development. They are therefore prone to hypoxic seizures, which can lead to long term synaptic development issues. AMPA receptors (AMPARs) are involved in the synaptic transmission of neurotransmitters in the central nervous system and one subset of these AMPARs are calcium-permeable (CP-AMPARs) because they lack the GluR2...
Summary: Researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development are highly motivated in seeking research co-development partners and/or licensees to further develop and commercialize PIKfyve phosphatidyl linositol kinase inhibitors for the treatment of pathogenic coronaviruses. An ideal partner would enter into both a Cooperative Research and Development Agreement (CRADA) and an exclusive license agreement towards commercialization of this technology. Description of Technology: The COVID-19 pandemic is a worldwide public health crisis with over 440 million confirmed cases and 6.0 million deaths as of March 2022. COVID-19 is caused by a novel coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While there are several vaccines available for COVID-19, there are few therapeutics available that specifically target SARS-CoV-2. Middle East respiratory syndrome...
Inflammatory processes associated with the over-production of tumor necrosis-alpha (TNF-alpha), a potent activator of the immune system accompany numerous neurodegenerative diseases. TNF-alpha has been validated as a drug target with the development of the inhibitors Enbrel and Remicade (fusion antibodies) as prescription medications. Both, however, are large macromolecules that require direct injection and have limited brain access. The classical drug, thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. The NIA inventors developed and assessed novel thio analogs of lenalidomide (Celegene's Revlimid and an analog of thalidomide) as immunomodulatory agents, with the potential to reduce chronic systemic and central nervous system inflammation. These compounds were synthesized and evaluated for their TNF-alpha inhibitory activity. This...
Inhibition of cyclin-dependent-kinase 7 (CDK7) for treatment of refractory castration-resistant prostate cancer (CRPC) through reduction of androgen receptor transcriptional activity. Applications: Treatment of advanced prostate cancer Treatment of advanced prostate cancer refractory to second generation anti-androgens Potential therapy for other hormonally driven cancers Inventors: Irfan Asangani.
Technology Overview: Roughly 12 million patients are exposed to heparin annually and up to 1% of these patients will develop heparin-induced thrombocytopenia/thrombosis (HIT), a life-threatening complication where patients make antibodies that bind to the heparin/PF4 complex, resulting in thrombosis and thrombocytopenia. The Greene lab has identified... Inventors: Mark Greene.
Natural bioactive peptides and hormones with thioamide substitutions at cleavage sites for improved pharmacokinetics Problem: Natural bioactive peptides are attractive lead pharmaceutical compounds, but peptides are subjected to rapid proteolysis in vivo. The majority of the time spent in peptide biologic drug development seeks to reduce this protein degradation, while maintaining activity. Solution: Researchers in the Petersson lab have developed a straightforward strategy to modify bioactive peptides in a minimally invasive manner. A single atom thioamide (O-to-S) substitution at the cleavage site of the peptide can decrease proteolysis rates up to 1000x to improve stability while maintaining peptide activity and function. The researchers applied this strategy to the incretin hormone glucagon-like peptide 1 (GLP-1), which stimulates insulin and suppresses glucagon secretion. GLP-1 is inactivated in vivo by dipeptidyl peptidase...
Currently available topical antibiotic formulations effectively eliminate bacteria at a wound site. Eliminating bacteria in the wound also eliminates the molecular signals present in bacterial DNA that stimulate the immune system's wound healing processes. Without these signals, the rate of wound healing is diminished. The present technology provides a means of improving the activity of topical antibiotics by supplementing the antibiotic formulation with immunostimulatory oligodeoxynucleotides (ODN). These ODN express the CpG motifs present in bacterial DNA and safely mimic the immune stimulation induced by bacterial DNA. The formulation may be applied directly to a wide variety of wounds to skin (such as traumatic, burn, or surgical wound, or the eyes (such as corneal abrasions) to effectively eliminate infection and stimulate rapid healing of the wound . Competitive Advantages: Eliminates wound site bacteria while retaining immune...
An effective, differentiated, and targeted therapeutic strategy for the treatment of inflammatory skin diseases such as psoriasis, atopic dermatitis, and hidradenitis suppurativa.
Topical LSD1 inhibition can treat skin diseases that include cutaneous squamous cell carcinoma (cSCC), actinic keratoses, and viral warts. Problem: Current treatment options (i.e. cryotherapy, laser therapy, surgery, chemotherapy) for skin diseases such as cSCC, actinic keratoses, and viral warts are often non-targeted and destructive, and can cause toxicity and damage to local tissue. In addition, treatment of larger and deeper lesions is associated with permanent scarring or disfigurement. Solution: The inventors developed a topical targeted LSD1 inhibitor that effectively treats skin lesions without harming local tissue. Inventors: Brian Capell, Napasorn (Nina) Kuprasertkul.
Chronic leg ulcers are a debilitating vasculopathic complication for some patients with sickle cell disease (SCD). Prevalence of leg ulcers varies based on age and geographic location; about 5-10% of all SCD patients may suffer leg ulcers. These leg ulcers are painful, result in infections, hospitalization, disability, and negatively impact the patient’s social and psychological wellbeing on an ongoing basis. Until recently, patients with SCD only had one drug treatment option: hydroxyurea, which was approved by the Food and Drug Administration (FDA) in 1998 in adults and in 2017, in children age 2 and older. However, there are no FDA-approved treatments specifically to treat SCD ulcers. The ulcer may take months or even years to heal. Opioid drugs are often administered to relieve intense pain symptoms, but the opioids do not treat the underlying wound conditions and carry addiction risks with chronic use. Thus, there is an unmet...
Treatment method for autoimmune diseases such as diabetes, multiple sclerosis, atherosclerosis, and rheumatoid arthritis using skin application of a vitamin D analog where topical treatment leads to systemic immunoregulation. Problem: Immunomodulatory drugs are typically administered systemically and often lead to severe side effects. Moreover, intravenous injections of such drugs are burdensome for patients and drive additional cost and risks. Whenever treatment involves biological compounds it further increases the cost and requires special storage, shipping, and handling. Solution: Many inflammatory diseases are mediated by inappropriately activated T cells. Regulatory T cells (Tregs), on the other hand, limit such inappropriate T cell activation, and prevent inflammatory diseases. Dr. Kambayashi has discovered that topical administration of a vitamin D3 analog MC903 leads to the release of keratinocyte-derived thymic stromal...
A significant challenge in developing therapies for the treatment and prevention of cancer has been the discovery, selection, and exploitation of antigens. Researchers at the National Institute on Aging (NIA) have partially circumvented this issue in their development of novel strategies for rendering weakly or non-immunogenic, shared antigens immunogenic, or able to produce an immune response. These strategies use proinflammatory chemokines to deliver antigens to immature dendritic cells (DCs) by targeting chemokine receptors differentially expressed on antigen presenting cells (APCs). Their work builds upon the discovery that tumor-associated, embryonic antigens (e.g., OFA-iLRP) – though non-antigenic alone – are effective for the treatment and/or prevention of cancer when linked to a chemoattractant ligand. Examples of such ligands include proinflammatory chemokines such as MIP3α/CCL20 or β-defensin mDF2β. Multiple vaccines may be...
Transformation-Associated Recombination (TAR) cloning in yeast is a unique method for selective isolation of large chromosomal fragments or entire genes from complex genomes without the time-consuming step of library construction. 1 The technique involves homologous recombination during yeast spheroplast transformation between genomic DNA and a TAR vector that has short (approximately 60bp) 5’ and 3’ gene targeting sequences (hooks). Further, because up to 15% sequence divergence does not prevent recombination in yeast, TAR cloning is highly efficient for isolation of gene homologs and synthenic regions. Using this technology, chromosomal regions up to 250kb can be rescued in yeast as circular YACs within 3-5 working days. . NIH researchers Drs. Larionov, Kouprina and Resnick have championed the use of this technology and TAR cloning has been used to efficiently isolate haplotypes, gene families 4 as well as genomic regions which are...
Available for licensing is a mouse model that constitutively expresses human interleukin-21 (IL-21). Traditionally, human IL-21 transgenic mouse models are difficult to produce as those with high IL-21 levels exhibit growth retardation and die before sexual maturity. The investigators generated transgenic mice that express human IL-21, which can stimulate murine cells in vitro thereby providing an accurate model to elucidate IL-21's role in immunity, immune disorders, and cancer. IL-21 is a type I cytokine whose receptor is expressed on T, B, and natural killer cells. IL-21 has pleiotropic actions ranging from augmenting the proliferation of T cells to driving the differentiation of B cells into memory cells and terminally differentiated plasma cells. Moreover, IL-21 has anti-tumor activity by augmenting natural killer cell activity. This mouse model allows studying human IL-21 in vivo and its role in a variety of diseases such as...
Researchers at NIH have generated transgenic mice in which the M3 muscarinic receptor is overexpressed in pancreatic beta cells. This was done by placing the receptor gene under the control of the 650 bp rat insulin promoter II (RIP II). The resulting mice show a pronounced increase in glucose tolerance and enhanced plasma insulin levels. Strikingly, these mutant mice were resistant to diet-induced glucose intolerance and hyperglycemia. Commercial applications: Diabetes research, especially type II Diabetes. Competitive advantages: These transgenic mice overexpress the M3 muscarinic acetylcholine receptor only in pancreatic beta cells but notably are resistant to diet-induced glucose intolerance and hyperglycemia Source institute: NIDDK. Inventors: Wess, Jurgen.
This technology relates to novel animal models of several human bone diseases that have been linked to enhanced BMP signaling. More specifically, this mouse model expresses a mutant receptor for BMP, known as Alk2 that is always actively signaling. This receptor is under the control of the Cre-loxP system, which allows control of expression of the mutant Alk2 in both a developmental and tissue-specific manner. As a result, the enhanced signaling conditions exhibited in multiple human bone-related diseases can be studied with the same animals. Commercial applications: The mouse model can be applied to the study of BMP signaling-related human diseases such as fibrodysplasia ossificans progressiva, which involves the postnatal transformation of connective tissue into bone. Another example of BMP signaling-related disease is Craniosynostosis, which involves the premature closing of the sutures in childhood so that normal brain and skull...
Q490L point mutation was introduced into the rat M3 muscarinic receptor cDNA to confer persistent, constitutive (ligand-independent) activity. Expression of the M3 receptor mutant was placed under the control of a 650 bp fragment of the rat insulin promoter II (RIP II) to limit expression to the islet beta cell. Commercial applications: Diabetes research, especially type II Diabetes. Competitive advantages: Beneficial metabolic effects of this mouse model include high basal insulin secretion, improved glucose tolerance, increased serum insulin, and resistance to high-fat diet-induced glucose intolerance and hyperglycemia. Source institute: NIDDK. Inventors: Wess, Jurgen.
Transgenic mouse model expressing a human uromodulin mutant mimicking hereditary human mutant uromodulin caused kidney diseases for testing diagnostics and therapy.
Problem: Urease is an enzyme found in human gut bacteria that hydrolyzes urea into ammonia. High levels of bacterial urease are associated with inflammatory bowel disease (IBD). Moreover, the increased ammonia resulting from urease activity can worsen symptoms for patients dealing with hyperammonemia – a condition associated with severe consequences... Problem: Urease is an enzyme found in human gut bacteria that hydrolyzes urea into ammonia. High levels of bacterial urease are associated with inflammatory bowel disease (IBD). Moreover, the increased ammonia resulting from urease activity can worsen symptoms for patients dealing with hyperammonemia – a condition associated with severe consequences such as brain edema, neurological impairment, liver dysfunction, and even death. Despite available treatments, managing IBD and hyperammonemia remains challenging as many patients develop treatment resistance. Solution: Bacterial urease...
This invention describes construction and initial functional testing of engineered chimeric antigen receptors transduced into human T-cells (CAR-T cells) for selective killing of melanocytes and melanoma cells. Applications: CAR T-cell based treatment is an option to treat invasive melanoma as it causes regression of the tumor by selectively killing melanoma cells and melanocytes. Can provide an alternative treatment for patients with advanced metastatic melanoma and for patients on whom immunotherapy/check point inhibitors does not work. Inventors: Todd Ridky.
Problem: While the 5-year relative survival rate for patients with local or regional prostate cancer is nearly 100%, the 5-year relative survival rate drops to 32% for patients with metastatic or advanced disease. These patients may initially respond to available therapies, but most patients will develop therapy resistance and succumb to disease. Solution: A... Problem: While the 5-year relative survival rate for patients with local or regional prostate cancer is nearly 100%, the 5-year relative survival rate drops to 32% for patients with metastatic or advanced disease. These patients may initially respond to available therapies, but most patients will develop therapy resistance and succumb to disease. Solution: A CAR construct that targets specific sugar-bearing prostate cancer cells and a subset of breast cancer cells. Inventors: Mark Greene, Michael Milone.
Ulcerative colitis (UC) is a chronic inflammatory disease of the colorectum and affects approximately 400,000 people in the United States. The cause of UC is not known, although an abnormal immunological response to bacterial antigens in the gut microflora is thought to be involved. Present treatments for UC include anti-inflammatory therapy using aminosalicylates or corticosteroids, as well as immunomodulators and diet. However, 25-40% of ulcerative colitis patients must eventually have their colons removed due to massive bleeding, severe illness, rupture of the colon, risk of cancer or due to side effects of corticosteroids and novel treatments are still actively being sought. NIH scientists and their collaborators have used a mouse model of experimental colitis (oxazolone colitis, OC) to show that IL-13, a Th2 cytokine, is a significant pathologic factor in OC and that neutralizing IL-13 in these animals effectively prevents...
Problem: Glaucoma is the number one cause of irreversible blindness worldwide. High pressure in the eye can lead to optic nerve damage, which can progress to permanent vision loss. For this reason, reduction of intraocular pressure is the main therapeutic mechanism available. Unfortunately, glaucoma can continue to progress even in patients with normalized... Problem: Glaucoma is the number one cause of irreversible blindness worldwide. High pressure in the eye can lead to optic nerve damage, which can progress to permanent vision loss. For this reason, reduction of intraocular pressure is the main therapeutic mechanism available. Unfortunately, glaucoma can continue to progress even in patients with normalized intraocular pressure. Therefore, there is an urgent need for the development of new therapeutic approaches with distinct mechanistic targets that prevent vision loss in glaucoma patients. Solution: Targeting glucagon-like...
Microduplications of the GPR101 gene (located on chromosome Xq26.3 and encodes a G-protein coupled receptor) can result in an excess of growth hormone causing gigantism, that has an onset in early childhood. It is also associated with the growth of sporadic growth hormone producing adenomas in some patients with acromegaly. Current therapies (such as surgical resection of tumors or treatment with somatostatin analogs) for acromegaly, gigantism and other disorders of pituitary hormone hypersecretion can be ineffective, thereby creating a need for alternative therapies in this space. The inventors at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) have developed a cell line that stably over-expresses GPR101. Agents which inhibit the expression the GPR101-encoded protein or the biological activity of the protein can be used to treat gigantism. Alternatively, agents that increase expression of...
Albinism (also called achromia, achromasia, or achromatosis) is a congenital disorder characterized by the complete or partial absence of pigment in the skin, hair and eyes due to absence or defect in any one of a number of proteins involved in the production of melanin. Certain forms of albinism are known to be due to mutations in tyrosine metabolism. In oculocutaneous albinism (OCA), pigment is lacking in the eyes, skin and hair. In ocular albinism, only the eyes lack pigment. Patients with albinism experience varying degrees of vision loss associated with foveal hypoplasia, nystagmus, photophobia and/or glare sensitivity, refractive errors, and abnormal decussation of ganglion cell axons at the optic chiasm. Current treatment options for vision problems caused by albinism are limited to correction of refractive errors and amblyopia, low vision aids, and (in some cases) extraocular muscle surgery. Nitisinone (NTBC) is an...
Castrate-resistant prostate cancer (CRPC) is characterized by androgen-independent cancer cells that have adapted to the depletion of hormones and continue to grow. Abnormal androgen receptor signaling is known to drive advanced castrate-resistant prostate cancer. The small molecule compounds of this invention are antiandrogens that target androgen receptor signaling in both androgen-independent and androgen-sensitive androgen receptor activity, and androgen receptors that are resistant to the current antiandrogens available. Unlike the currently available antiandrogens, the new small molecules induce androgen receptor degradation and cell death in prostate cancer cells. Further, these compounds and methods can also induce degradation of other steroid hormone receptors demonstrating the possibility of treating a wider range of cancers. Competitive Advantages: First small molecule antiandrogen treatment. Causes cell death, not just...
Disorders of adult beta-globin synthesis, which include sickle cell disease (SCD) and beta-thalassemia, are the most common monogenic disorders in the world. While the curative potential of bone marrow transplantation has been demonstrated, this approach is limited to a small fraction of affected patients due to the requirement for an HLA-matched donor, the highly specialized approach that requires critical infrastructure, and the high cost. Scientists at the National Heart, Lung, and Blood Institute (NHLBI), have developed lentiviral vectors encoding shRNA to Rio-Kinase 3 (RIOK3) that decrease expression of RIOK3, leading to more robust fetal hemoglobin expression. Commercial applications: Treatment of beta-globinopathies such as Sickle Cell Disease.. Competitive advantages: Increase fetal hemoglobin expression.. Novel and more cost-effective treatment. Source institute: NHLBI. Inventors: Tisdale, John, Gudmundsdottir, Bjorg,...
Docket# S4039 Technology: Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus(KSHV) are human γ-herpesviruses associated with a broad spectrum of B-cell lymphomas typically in immune-compromised populations. There are no drugs which can specifically target EBV/KSHV-associated B-cell tumors. Using a High-throughput Screen... Inventors: Erle Robertson.
National Institutes of Health researchers have developed knockout mice that do not express Tristetraprolin (TTP). TTP is an AU-rich element (ARE) binding protein and the prototype of a family of CCCH zinc finger proteins. AREs were identified as conserved sequences found in the 3’ untranslated region (3’ UTR) of a variety of transiently expressed genes including early response genes, proto-oncogenes, and other growth regulatory genes. AREs function as instability sequences that target ARE-containing transcripts for rapid mRNA decay. TTP functions by binding directly to the ARE sequence contained in the TNF-alpha mRNA, which destabilizes and mediates rapid decay of the TNF-alpha mRNA. More recent studies demonstrate TTP’s ability to downregulate IL-2 gene expression. TTP knockout mice appear normal at birth but soon develop inflammatory arthritis, dermatitis, cachexia, autoimmunity, and myeloid hyperplasia. Almost all aspects of these...
Novel A 3 adenosine antagonists available for licensing. A 3 receptors are particularly highly expressed in inflammatory cells, making it a potentially desirable target for inflammatory diseases. This technology relates to highly specific antagonists and partial agonists of A 3 adenosine receptors, which are negatively coupled to adenylate cyclase and have been broadly implicated in inflammation, cardiovascular disease, endocrine conditions and cancer. Further, A 3 adenosine receptors have been implicated in asthma and glaucoma. Competitive advantages: There are four known subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ). All are positively or negatively linked to cAMP, but have different distributions and different therapeutic potentials. In particular, the use of A 1 and A 2 selective ligands has been limited by the ubiquity of expression of the receptors throughout the body and the resultant side effects. On the other...
Bacterial toxins such as cholera toxin and diphtheria toxin catalyze the ADP-ribosylation of important cellular target proteins in their human hosts, thereby, as in the case of cholera toxin, irreversibly activating adenylyl cyclase. In this reaction, the toxin transfers the ADP-ribose moiety of Nicotinamide Adenine Dinucleotide (NAD) to an acceptor amino acid in a protein or peptide. ADP-ribosylation leads to a peptide/protein with altered biochemical or pharmacological properties. Mammalians proteins catalyze reactions similar to the bacterial toxins. The ADP-ribosylated proteins represent useful pharmacological agents, however, their use is limited by the inherent instability of the ADP-ribose-protein linkage. The NIH announces a new technology wherein recombinant proteins are created that substitute tryptophan for an arginine, thereby making the protein more stable, and better suited as agents for therapeutic purposes. The...
This CDC invention entails methods and apparatuses for in situ testing seal integrity and improved operation of respiratory masks (respirators). A variety of external factors, such as individual face shape, user environment, mask age and material used to construct the respirator, can lead to device malfunction and failure to sufficiently protect a user. To address these limitations, this invention relies on ultrasonic wave detection to assess face seal quality and other potential leak paths, as needed. Airborne ultrasound travel through atmosphere and will travel through respirator leaks. Applying this phenomena to occupational health and safety, CDC researchers have developed novel ultrasonics technology to identify and quantify respirator seal leakage in real-time. Small, low power consuming, and inexpensive apparatuses and methods for generating and detecting ultrasound may be easily obtained and customized for a given respirator...
CDC researchers have developed an assay for detection and diagnosis of poxviruses within clinical samples or from lab culture-systems. The assay specifically targets chordopoxviruses (except avipoxviruses) for PCR-based identification; an improvement upon the current standard of cell culturing methodologies. Individual chordopoxvirus species can cause disease in humans (e.g., vaccinia, cowpox, monkeypox/Molluscum contagiosum) and animals (e.g., sheeppox, myxoma, swinepox, mule deer pox, tanapox/Orf virus, Bovine popular stomatitis virus). Some poxvirus species impart unique and obvious symptoms making them easy to diagnose, while many others are clinically ambiguous. For instance, parapoxvirus infections are often misdiagnosed as cutaneous anthrax, which unnecessarily contributes to overuse of antibacterial agents. There is therefore a demonstrated need to develop better diagnostic tools to detect and properly identify the agent of...
Small molecules targeting utrophin mRNA untranslated regions overcome post-transcriptional repression Problem: Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder that affects approximately 1 in 3500 males worldwide. DMD is caused by mutations in the DMD gene that lead to severe reduction or loss of dystrophin protein. Without appropriate dystrophin expression, patients experience progressive muscle degeneration and weakness that leads to early death around the third decade of life. While corticosteroids can be used to slow disease progression, there is no definitive cure for DMD. Solution: In the absence of dystrophin, the autosomal homolog utrophin has been shown to partially replace dystrophin function. Utrophin is highly expressed during fetal development, but is actively down-regulated in adult muscle through numerous post-transcriptional repression mechanisms. Rather than supplement utrophin expression using...
ImmunologyNeurologyRare DiseaseInfectious DiseaseSmall MoleculeBiologicCell/Gene TherapyAI / ML
Summary: NCI seeks research co-development and/or potential licensees for a potential novel treatment for triple-negative breast cancer (TNBC) with acetalax (oxyphenisatin acetate). Description of Technology: Triple negative (progesterone receptor (PR)-, estrogen receptor (ER)-, human epidermal growth receptor 2 (HER2)-) breast cancer (TNBC) is an aggressive subtype that affects 15-20% of the 1.7 million cases of breast cancer occurring annually. Currently, standard treatments of TNBC include cytotoxic chemotherapies, surgery, and radiation. However, TNBC readily becomes resistant to chemotherapy, and those with TNBC are more likely to have a recurrence or die within five years compared to those with other breast cancer types. Therefore, there is a need for safer and more effective TNBC treatments to improve patient outcomes. Investigators from the National Cancer Institute (NCI) and collaborating institutions have identified the...
High expression of CD47, a cell surface receptor on several types of cancer cells, has been identified as a ‘don’t eat me signal’ that inhibits their killing by macrophages or NK cells. Conversely, the CD47 antibody B6H12 that blocks SIRPα binding enhances macrophage-dependent clearance of tumors in several mouse models, although others have shown that such clearance can be independent of SIRPα signaling. Cancer stems cells (CSCs) are tumorigenic cells that are difficult to target with conventional chemotherapies due to their undifferentiated state. Stem cells also play an important role in the pathogenesis of cancer. CSCs have been reported to express elevated CD47 levels, but the role of CD47 in directly regulating cancer stem cell function has not been examined. Researchers at the National Cancer Institute's Laboratory of Pathology found that the absence of CD47 enhances stem cell renewal in vitro and in vivo by increasing...
The vast majority of people infected with Hepatitis C Virus (HCV) will have chronic infection. Over decades, this can lead to liver disease and liver cancer. In fact, HCV infection is the leading cause of liver transplants in the U.S. Several new drugs have recently come into the market that will likely change the HCV treatment paradigm. However, the effectiveness of these new drugs can vary depending on the HCV genotype. Thus, there is still the need for additional new therapeutics against HCV. The subject technology are small molecule compounds identified using a novel cell-based high throughput assay of HCV infection. The compounds are antihistamines that show potent antiviral properties against HCV. One advantage of these compounds is that they are already on the market for the treatment of allergic reactions and, thus, have been used extensively in humans and have excellent safety profiles with known pharmaceutical properties....
Description of Technology: Certain members of the cucurbitacin and Withanolide family have been identified that can sensitize some tumor cell lines to cell death (apoptosis) on subsequent exposure of the cells to pro-apoptotic receptor agonists (PARAS) of the TRAIL "death receptors". These PARAS include TRAIL itself, and agonist antibodies to two of its receptors death receptor-4 (DR4 or TRAIL-R1) and death receptor 5 (DR5, TRAIL-R2). The protein TRAIL has a very interesting characteristic that it can preferentially cause death of cancer cells whereas normal non-transformed cells are unaffected. Thus use of TRAIL or agonist antibodies to its so-called "death receptors" has been a current focus in cancer therapy. Potential Commercial Applications: Use of the compounds with known TRAIL or agonist antibodies such as Mapatumumab or in combination with immunotherapeutic approaches for the treatment of cancer.. Competitive Advantages:...
This CDC developed optimization technology allows one to characterize the behavior of the coefficient of variation (CV) for a range of mass spectrometer machine settings. Surface-enhanced laser desorption/ionization (SELDI) and matrix-assisted laser desorption/ionization (MALDI) are used for the early detection of numerous diseases, for example cervical cancer . A critical step in the analytical process is the optimization of experiment and machine settings to ensure the best possible reproducibility of results, as measured by the CV. The high cost of this procedure includes man hours spent optimizing the machine, opportunity cost, materials used, and spent biological samples used in the optimization process. This technology can be used to optimize the CV with the following advantages over conventional methods: 1) no need to use biological samples, 2) fewer materials are consumed in the process, 3) improved CV and thus more...
OphthalmologyOncologyNeurologyInfectious DiseaseImmunologyCardiometabolicInflammationBiologicDiagnostic / BiomarkerAI / ML
Interleukin (IL)-34 is a homodimer that is produced mainly by keratinocytes, neuronal cells and regulatory T cells (Tregs). It is believed to play important roles in chronic inflammation and the homeostasis of microglia. Currently, there is no effective treatment for many types of retinal degeneration. An improved treatment of autoimmune uveitis is also needed, as current uveitis treatment primarily uses steroidal anti-inflammation medication, which may produce significant unwanted side effects in long-term use. The inventors at the National Eye Institute (NEI) found that various retinal degeneration and uveitis models in mice with congenital mutations affecting vision have varying degrees of IL-34 deficiency in their intraocular environment. This suggests that IL-34 may be essential in modulating autoimmune uveitis and retinal degeneration. Therefore, Adeno-associated Virus (AAV) AAV8-IL-34-mediated gene therapy or other extended...
A novel treatment for rare disease Friedreich ataxia using p38 or MK2 kinase inhibitors Problem: Currently there are no approved drugs to treat FA and the resultant disability, prolong the life of a FA patient, or cure the disorder. Solution: Work in the Wilson Lab led to a surprising discovery that p38 MAP kinase inhibitors (many of which are in clinical trials for various indications) rescue disease phenotypes of cells affected by FA. This suggests that the p38 kinase (or MK2) can be possible targets for therapeutic intervention in Friedreich ataxia.rules, are highly specific to FA, and are active in the low nanomolar range. Several optimized modifications of the lead compounds have been generated. Inventors: Robert Wilson.
Summary: The NICHD is seeking licensees for development of Carboxypeptidase E (CPE) as a therapy for MCI or AD. Description of Technology: There is no known cure for Alzheimer’s disease, a brain disorder that severely affects memory, thinking, learning, and organizing skills. It eventually decreases a person’s ability to carry out simple, daily activities. It is predicted that over 14 million Americans will develop Alzheimer’s without effective treatment options. Mild cognitive impairment (MCI) is a stage prior to Alzheimer’s when memory problems become noticeable. A patient’s ability to function and live independently remain intact as the brain compensates for disease-related changes. Disease symptoms worsen over a period that may progress over 10 years. In some people, MCI can hold steady at this stage. However, people with MCI are at high risk for progressing to dementia. Alzheimer’s disease is the most common form of dementia. MCI...
Summary: The NIA seeks co-development partners and/or licensees for the further pre-clinical and clinical development of TTI-101, hydroxychloroquine, and Dasatinib to treat Alzheimer’s disease. Description of Technology: There are no effective treatments for Alzheimer’s disease (AD), a progressive brain disease that slowly destroys a person’s memory, cognitive skills and ability to carry out the simplest tasks. AD affects more than 5 million individuals in the United States and ranks as the sixth leading cause of death. The ε4 allele of the apolipoprotein-E (APOE) gene is the strongest genetic risk factor for sporadic or late-onset AD. Heterozygous carriers of the ε4 allele are at three-to-four times greater risk; homozygous carriers are at ten times greater risk. In fact, APOE ε4 carriers accumulate AD neuropathology early in adulthood with earlier age onset of AD compared with ε4 non-carriers. Researchers at the National Institute...
This technology includes a small molecule drug (VDAC inhibitor, also known as VBIT4) that may be useful for inhibiting lupus disease. To test lupus animal model, VBIT4 was continuously administered for 5 weeks to mice and there was no mortality or clinical symptoms in these animals. Additionally, VBIT4 treatment blocked the development of skin lesions and alopecia of the ears and face, and suppressed the thickening of the epidermis that accompanies leukocyte infiltration. Supporting these results, VBIT4 treatment reduced both spleen and lymph node weight, as well as significantly diminished the typical symptoms of lupus. Our findings demonstrated that VBIT4 may be an effective drug for the treatment of lupus. Commercial applications: Treatment for lupus. Competitive advantages: Current agents used for the treatment of lupus have several side effects and the VDAC axis exploits a completely new target in lupus therapy amenable via the...
One problem with the development of immunotherapy for cancer or other diseases is the inability to stimulate a sufficient immune response in patients to tumor associated antigens. The Linker Adapted for T Cell Signaling molecule (LAT) has been shown to be an important molecule in T cell signaling. The inventions described and claimed in this patent application illustrate a new supportive role for LAT which may be harnessed to improve a patient's immune response to tumor-associated antigens. A number of approaches to improving the immune response in cancer immunotherapy have been investigated. One such approach is to be able to influence the potency of T Cell Signaling. This invention exploits the role of LAT in T Cell signaling and provides a means to create a more intense and effective T Cell response. This would have the end result of improving the overall response of a patient's immune system to the presence of tumor-associated...
Summary: The National Eye Institute seeks research co-development partners and/or licensees for a therapy using an FDA-approved small molecule drug reserpine (and related compounds especially halofantrine) that prevents photoreceptor cell death in retinal degenerations. Description of Technology: Inherited Retinal Degenerations (IRD), such as Leber Congenital Amaurosis (LCA) and retinitis pigmentosa (RP), are characterized by a progressive loss of photo-sensitive cells in the retina. Most forms of IRD have no therapeutic options available due to their genetic heterogeneity and/or lack of mechanistic understanding. In particular, LCA represents roughly 5% of all retinal dystrophies and results in severe vision loss at an early age. There is an FDA-approved treatment for one form of LCA caused by mutations in the RPE 65 gene. This involves injection of an adenovirus vector containing the normal copy of the RPE65 gene. Long-term data for...
This invention relates to a VAC-BAC shuttle vector system for the creation of recombinant poxviruses from DNA cloned in a bacterial artificial chromosome. A VAC-BAC is a bacterial artificial chromosome (BAC) containing a vaccinia virus genome (VAC) that can replicate in bacteria and produce infectious virus in mammalian cells. Commercial applications: VAC-BACs can be used to modify vaccinia virus DNA by deletion, insertion or point mutation or add new DNA to the VAC genome with methods developed for bacterial plasmids, rather than by recombination in mammalian cells.. It can be used to produce recombinant vaccinia viruses for gene expression.. It can be used for the production of modified vaccinia viruses that have improved safety or immunogenicity.. Competitive advantages: VAC-BACs are clonally purified from bacterial colonies before virus reconstitution in mammalian cells.. Manipulation of DNA is much simpler and faster in bacteria...
Non-replicating viral delivery of shVASH1 to treat heart failure. Problem: Heart failure (HF) is condition in which the heart cannot pump enough blood throughout the body to meet its need. Approximately 6 million American adults live with the condition, and close to 400,000 people die from it annually. Mainstay treatment for HF are lifestyle changes and medications that include ACE inhibitors, beta blockers, diuretics, and sodium-glucose cotransporter-2 inhibitors. Despite several treatment options, the 5-year mortality rate remains high at approximately 75%. Solution: One hallmark of HF is increased stiffness of cardiomyocytes (CM), which is due to the detyrosination of cardiac microtubules. Vasohibin-1 (VASH1) is an enzyme that detyrosinates cardiac microtubules. The inventors discovered that VASH1 depletion was sufficient to reduce microtubule detyrosination and restore CM function. Inventors: Alexey Bogush, Kenneth Margulies,...
Research scientists at CDC have developed compositions and methods that can be used to develop attenuated vaccines having well-defined levels of replicative fitness and enhanced genetic stabilities. Infections by intracellular pathogens, such as viruses, bacteria, and parasites, are cleared in most cases after activation of specific T-cell immune responses that recognize foreign antigens and eliminate infected cells. Vaccines against those infectious organisms traditionally have been developed by administration of whole live attenuated or inactivated microorganisms. Although research has been performed using subunit vaccines, the levels of cellular immunity induced are usually low and not capable of eliciting complete protection against diseases caused by intracellular microbes. CDC inventors discovered that replacement of one or more natural (or native) codons in a pathogen with synonymous unpreferred codons can decrease the...
This technology includes a micro-engineered “thyroid-on-a-chip” that combines human thyroid organoids with integrated micro-vasculature to replicate the gland’s native blood flow and 3-D architecture, enabling rapid, patient-specific drug screening. By permitting real-time perfusion of nutrients, hormones, and immune cells, the platform yields more physiologically relevant data than conventional static cultures or animal surrogates. Its modular design accommodates cells from individual patients, helping clinicians predict therapeutic response and tailor treatment for thyroid cancers and autoimmune disorders. In pharmaceutical R&D, the chip shortens pre-clinical timelines by providing actionable efficacy and toxicity read-outs within days. Overall, the system offers a high-fidelity bridge between benchtop discovery and clinical decision-making, addressing an unmet need for robust human thyroid models. Commercial applications:...
There are five known Ebolavirus species: Ebola virus (Zaire ebolavirus); Sudan virus (Sudan ebolavirus or SUDV); Taï Forest virus (Taï Forest ebolavirus, formerly Cote d'Ivoire ebolavirus); Bundibugyo virus (Bundibugyo ebolavirus); and Reston virus (Reston ebolavirus). Last year an ebolavirus outbreak resulted in 164 cases and 55 deaths. While there is an FDA-approved Ebola virus vaccine authorized for use against Ebola virus infections, ERVEBO, this vaccine is not effective against SUDV due to the significant variation between Ebola virus and SUDV. ERVEBO is a live recombinant viral vaccine consisting of a vesicular stomatitis virus (VSV) backbone deleted for the VSV envelope glycoprotein and substituted with the envelope glycoprotein of the Ebola virus (Kikwit 1995 strain). This invention provides a VSV-based vaccine expressing the SUDV-Gulu GP (VSV-SUDV). The VSV backbone of this vaccine appears to be very similar to the VSV...
Chikungunya virus (CHIKV) is mosquito-borne alphavirus endemic in Africa, India, and Southeast Asia. In 2013 CHIKV infection has also emerged in the Caribbean and a pandemic of CHIKV has re-emerged in the Philippines following Typhoon Haiyan. Currently, there is no vaccine available for the prevention of CHIKV infection and no specific therapy exists to treat the illness. Researchers at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID) have developed a CHIKV Viral Like Particle (CHIKV VLP) vaccine based on plasmid expression vectors encoding structural proteins of the CHIKV virus, which gave rise to CHIKV VLPs in transfected cells. The CHIKV VLPs consist of the core, E1 and E2 proteins and are similar in buoyant density and morphology to replication-competent CHIKV virus. Immunization with CHIKV VLPs elicited neutralizing antibodies against envelope proteins from different CHIKV...
Rift Valley fever (RVF) virus primarily infects animals but also has the capacity to infect humans. The disease causes abortion and death among RVF-infected livestock, resulting in substantial economic loss to people living in many parts of Africa and Arabian Peninsula. Currently, there is no commercial vaccine for RVF. CDC scientists have developed a RVF virus replicon particle (VRP) vaccine candidate. Research findings revealed that immunization of mice with a single dose of the RVF-VRP was found to be safe and elicited immune response that offered 100% protection following exposure to lethal dose of virulent virus. RVF-VRPs have the potential to become effective and efficient RVF vaccines in livestock animals and humans. Commercial applications: Rift Valley fever vaccine for livestock and/or humans. VRPs may serve as useful laboratory tool to study the basic mechanisms of virus replication, assembly, kinetics, and virus maturation....
The National Cancer Institute's Protein Expression Laboratory seeks parties interested in licensing the novel delivery of RNA to mammalian cells using virus-like particles. Current methods of delivering proteins or RNA to mammalian cells are limited by a lack of target specificity and toxicity, among other shortcomings. NCI researchers have created novel virus-like particles (VLPs) that are capable of binding to and replicating within a target mammalian cell, including human cells. The claimed VLPs are safer than viral delivery because they are incapable of re-infecting target cells. The present VLPs can optionally comprise inhibitory recombinant polynucleotides, such as microRNA, antisense RNA or small hairpin RNA, to down regulate or turn off expression of a particular gene within the target cell. Alternatively, recombinant polynucleotides packaged within VLPs can comprise a gene encoding a therapeutic protein so as to enable...
Vitamin D receptor (VDR) is a nuclear receptor that is activated by calcitriol, the active form of vitamin D. It is best known for regulating dietary calcium uptake necessary for bone growth, but it also affects cell proliferation and differentiation. Therefore, it was thought that treatment with calcitriol or its derivatives could be useful to treat the uncontrolled proliferation typical of cancer cells. However, this approach has been unsuccessful to date because it leads to toxic levels of calcium in the blood. This invention relates to derivatives of calcitriol that can block cell growth without harmfully raising calcium levels. Specifically, these compounds act as antagonists of VDR blocking its ability to stimulate cell proliferation. This technology can be useful in treating breast cancer or other malignancies. Commercial applications: Potential drugs for treating breast cancer and possibly also prostate cancer, colorectal...
Mutation in gene A34R can regulate the release of progeny virions from the surface of parental cells. Commercial applications: A research material that can be used in the development of assays, validation of products or in quality control.. Competitive advantages: Speed up product development with NIH developed material that has already been tested and validated.. Source institute: NIAID. Inventors: Blasco, Rafael, Moss, Bernard.
Zika virus (ZIKV) is a flavivirus primarily transmitted by infected Aedes mosquitoes. Infection with ZIKV during pregnancy can affect the fetus causing microcephaly, neurological complications, and other birth defects. Adults are also at risk of developing Guillain-Barre syndrome and other neurological disorders from ZIKV infection. In response to the 2015-2016 Zika outbreak, CDC researchers developed new Zika virus chimeras that can be used for inactivated Zika vaccine candidates and faster Zika antibody (Ab) neutralization assay testing. CDC scientists successfully engineered cDNA clones for the chimeric constructs based on a West Nile (WN) Virus NY99 genetic backbone and recovered three fast-growth chimeric WN/Zika viruses. These chimeric viruses replicate significantly faster and produce a more uniform virus population than the parental wild-type Zika virus from cell culture. Future research will include inactivated vaccine...
Primary tumor reoccurrence often occurs following surgical resection in glioblastoma multiforme patients. Current hydrogel approaches deliver therapeutics using light or pH, but these approaches are limited by the tumor microenvironment. Researchers have developed an injectable hydrogel with unique materials that can be activated by X-ray irradiation for sustained, on-demand therapeutic delivery. These hydrogels can be loaded with CT contrast agents and therapeutic drugs without affecting their functionality, morphology, or injectability. Problem: Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancers. Patients diagnosed with GBM have a median survival of 14 months and two-year survival rate of 27%. These patients undergo extensive treatment, including surgical tumor resection followed by chemotherapy infusion and radiation, yet 70% of patients experience reoccurrence of the primary tumor. Injectable...
This technology includes a gene-based magnetic resonance imaging (MRI) reporter platform that harnesses adeno-associated virus (AAV) delivery of the metal transporter Zip14 to create image contrast wherever the gene is expressed. By driving Zip14 from cell-specific promoters, investigators obtain robust, long-lasting signal changes on standard clinical MRI sequences (e.g., MPRAGE and GRE), enabling real-time visualization of living cells and their gene-expression patterns. Because no external contrast agents, exotic pulse sequences, or tissue implantation steps are required, the system simplifies longitudinal studies and reduces safety concerns. The modular design supports rapid retargeting to other tissues, providing a scalable solution for tracking gene-therapy vectors, regenerative processes, or engineered cell therapies. Overall, Zip14-AAV reporters bridge the gap between molecular biology and routine radiology, opening a clear...
mEpoR-/- hEpoR+: The mouse Erythropoietin Receptor knockout that contains a human Erythropoietin Receptor transgene can be used to define the potency of recombinant erythropoietin preparations used to treat anemia associated with chronic kidney disease. Erythropoietin, acting by binding to Erythropoietin receptors (EpoR) on erythroid progenitor cells, is required for erythropoiesis. Absence of erythropoietin or the EpoR in mice interrupts erythropoiesis in the fetal liver and result in death at embryonic day 13.5. An 80-kb human EpoR transgene bred onto a mouse EpoR null background (provided by F. Constantini of Columbia University) restored effective erythropoiesis in the EpoR null mouse. Erythropoietin preparations made utilizing recombinant DNA technology are used in the treatment of anemia in chronic kidney disease and other critical illnesses. The mouse EpoR null mouse containing the human EpoR transgene can be used to define the...
A novel mRNA-based therapy that induces corneal endothelium regeneration to restore vision loss Problem: Corneal endothelial cells are critical for maintaining a clear cornea, mainly by pumping fluid out of the tissue. Decrease in number of these cells results in the clouding of the cornea that leads to vision loss. The standard of care for Fuchs Endothelial Corneal Dystrophy (FECD) is corneal transplantation. However, in addition to the procedure being invasive and costly, there is an immense shortage of cornea donors (approximately 1 cornea available for 70 needed). Solution: Induce proliferation of corneal endothelial cells to reverse loss of cells using mRNA therapeutics delivered directly into the eye. Inventors: Panteleimon Rompolas.
The integrity of the epidermis and mucosal epithelia is highly dependent on self-renewing stem cells and, therefore, is vulnerable to physical and chemical damage from common cancer treatments, such as radiation or chemotherapy. Consequently, many cancer patients undergoing these treatments develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Since current prevention and treatment options for mucositis are limited, providing only minor relief and no protection to stem cells, novel therapies are needed. The NIH inventors have recently discovered that the mammalian target of rapamycin (mTOR) mediates stem cells exhaustion in the skin and leads to progressive hair loss. More importantly, they have shown that mTOR inhibition reduces oxidative stress in the epithelial stem cells and mTOR inhibitors can be used to increase the re-populative capacity of tissue resident stem cells to maintain tissue...
Technology Overview: Many agents used for oncology are either vulnerable to enzymatic attack or are poorly water-soluble, making them difficult to deliver to a tumor site. This invention describes a novel pH-sensitive peptide-based nanoparticle which can provide a precisely targeted method for drug delivery. Rather than relying on uptake of the nanoparticle... Inventors: I-Wei Chen.
RNA interference (RNAi) is a biological response to double-stranded RNA that regulates expression of protein-coding genes and is a natural mechanism for gene silencing. Delivery of short, interfering RNA (siRNA) leads to RNAi of the targeted genes. Researchers at the National Cancer Institute (NCI), in collaboration with researchers at the University of California, Santa Barbara (UCSB), developed a tetrahedral-shaped RNA nanoparticle for the delivery of siRNA to activate RNAi. The tetrahedral RNA nanoparticle is comprised of four RNA nanorings as the “faces” of the tetrahedral scaffold. The tetrahedral RNA nanoparticles can contain up to twelve Dicer substrate RNA duplexes, enabling the simultaneous targeting of multiple genes with several siRNA copies. Competitive Advantages: Increased functional capacity of RNA nanoparticles. Can contain up to 12 targeting siRNAs while maintaining thermodynamic stability. Allows for substitution of...
