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| 9337 | Development of the αllbß3 Antagonist RUC-4 for the Treatment Myocardial Infarction (MI) and Congestive Heart Failure (CHF) | MI, known more commonly as a heart attack, is estimated to account for approximately 280,000 out-of-hospital deaths each year in the United States. Most of these events are preceded by warning symptoms such as angina (chest pain) or dyspnea (shortness of breath) that alert patients and others to the need for care. Patients typically present these warning symptoms 30 to 120 minutes prior to MI, providing a limited window of time for medical treatment that could lessen the severity of MI or prevent it entirely. Scientific Synopsis After warning symptoms present, several treatments that reduce the rate of disease and prevent MI-related death and the CHF that often develops post-MI may be administered. Of these, platelet integrin aIIbb3 antagonists can often produce dramatic benefits. Unfortunately, existing aIIbb3 antagonists all require intravenous (IV) administration, making them difficult to deliver in out-of-hospital, emergency-type settings. Additionally, some aIIbb3 antagonists have been shown to induce an undesired conformational change in the integrin receptor that “primes” the receptor to bind fibrinogen, and they may contribute to thrombocytopenia, a condition where the blood platelet count becomes too low. The goal of this project is to develop a novel aIIbb3 antagonist with properties that would allow it to be delivered more conveniently by auto-injection, the same technology used in EpiPens® and similar devices. By greatly improving the convenience of aIIbb3 antagonist delivery, the project team believes that the use of these agents in out-of-hospital settings would increase, thereby leading to a reduction in disease and death from MI and CHF. If such an agent bound the integrin receptor without inducing an undesired conformational change, the risk of thrombocytopenia should also be diminished. Medicinal chemistry efforts in the team’s laboratories have led to the discovery of lead compound RUC-4, a potent aIIbb3 antagonist with properties suitable for delivery by auto-injection. The project team initially identified the chemical starting point RUC-1 from high-throughput screening. Structure-guided optimization of that compound ultimately produced RUC-4, a potent aIIbb3 antagonist that binds integrin without inducing undesired conformational change. Importantly, RUC-4 displays high aqueous (water) solubility (>60 mg/mL) as well as other properties that should permit delivery by auto-injection. In a cell-based assay, RUC-4 potently and selectively inhibits the binding of fibrinogen to aIIbb3. In a mouse model of arterial thrombosis, RUC-4 produces a significant decrease in arterial occlusion compared with the vehicle. Current efforts are aimed at optimizing the salt form and formulation of RUC-4 to enable its advancement into clinical trials as a treatment for MI. This figure illustrates the chemical starting point, RUC-1, and optimized compound RUC-4. The bar graph in the center indicates the effect of RUC-4 on the binding of aIIbb3 (in red on the left) to fibrinogen and on the binding of aVb3 (in blue on right) to vitronectin, compared with control and several other agents. The line graph on the right indicates the effect of RUC-4 on arterial thrombosis induced by laser injury in mice, with the lines indicating the percentage of mice free from arterial occlusion after treatment with the vehicle (blue line on left) or RUC-4 (red line on the right). (Reprinted with permission from Li J, et al. A novel aIIbb3 antagonist for pre-hospital therapy of myocardial infarction. Arterioscl Thromb Vasc Biol. 2014;34(10):2321–9. Copyright 2014 Arteriosclerosis, Thrombosis, and Vascular Biology.) Lead Collaborators Craig J. Thomas, Ph.D., NCATS, NIH Jian-kang Jiang, Ph.D., NCATS, NIH Barry Coller, M.D., Rockefeller University Publications Li J, Vootukuri S, Shang Y, Negri A, Jiang J-k, Nedelman M, Diacova TG, Filizola M, Thomas CJ, Coller BS. RUC-4: A novel aIIbb3 antagonist for pre-hospital therapy of myocardial infarction. Arterioscl Thromb Vasc Biol. 2014;34(10):2321–9. Jiang J-k, McCoy JG, Shen M, LeClair CA, Huang W, Negri A, Li J, Blue R, Harrington AW, Naini S, David G III, Choi W-S, Volpi E, Fernandez J, Babayeva M, Nedelman MA, Filizola M, Coller BS, Thomas CJ. A novel class of ion displacement ligands as antagonists of the aIIbb3 receptor that limit conformational reorganization of the receptor. Bioorg Med Chem Lett. 2014;24(4):1148–54. Zhu J, Choi W-S, McCoy JG, Negri A, Zhu J, Naini S, Li J, Shen M, Huang W, Bougie D, Rasmussen M, Aster R, Thomas CJ, Filizola M, Springer TA, Coller BS. Structure-guided design of a high-affinity platelet integrin aIIbb3 receptor antagonist that disrupts Mg2+ binding to the MIDAS. Sci Trans Med. 2012;4(125):125ra32. Public Health Impact This project has yielded the optimized aIIbb3 antagonist RUC-4. This compound displays high water solubility across a range of pHs, and an overall profile that facilitates delivery by auto-injection in out-of-hospital settings. Current work is aimed at further optimizing RUC-4 to enable its advancement into human clinical trials as a treatment for MI. | Development of the αllbß3 Antagonist RUC-4 for the Treatment | Development of the αllbß3 Antagonist RUC-4 for the Treatment | ||||||
| 9336 | Development of an Activator of the Pyruvate Kinase Isoform M2 (PKM2) | Scientific Synopsis Cancer cells exhibit altered metabolism and use of extracellular nutrients, providing a unique strategy to affect tumor growth. Tumors are known to import significantly higher amounts of glucose compared with normal tissue and use glucose’s carbons as cellular building blocks for proliferation. Associated with this enhanced glucose uptake, also known as the Warburg effect, the expression of the M2 isoform of pyruvate kinase is a factor contributing to biosynthesis and tumor growth. Scientists at NCATS developed TEPP-46 (ML265), a small molecule activator of PKM2 with an intriguing mechanism of action. PKM2 must adopt a tetrameric quaternary structure to be active, and TEPP-46 binds at the interface between the monomers, promoting tight protein binding. In addition, PKM2 activation impairs cancer proliferation by interfering with tumors’ anabolic metabolism. TEPP-46 constitutes a valuable molecular probe to study the downstream metabolic effects of PKM2 activation. Image (a) shows an interaction between tetrameric PKM2 and TEPP-46. The four PKM2 monomers are represented in cartoon mode with different colors. The bound FBP and the activator molecules are colored black and red, respectively, and are shown as space-filling models in the middle. The interfaces between two monomers are indicated by dotted lines. Image (b) illustrates the interactions between TEPP-46 and the surrounding residues. The bound activator is colored yellow and represented by a ball-and-stick model. The residues from the two monomers that are involved in the interaction are colored green and cyan and labeled. Hydrogen bonds are shown by blue dashed lines with their distances indicated. (Reprinted with permission from Palsson-McDermott EM, et al. Pyruvate kinase M2 regulates HIF-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab. 2015;21(1):65–80. Copyright 2015 American Chemical Society. Lead Collaborators Craig J. Thomas, Ph.D., NCATS, NIH Matthew G. Vander Heiden, Ph.D., Massachusetts Institute of Technology Publications Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, van den Bosch MW, Quinn SR, Domingo-Fernandez R, Johnston DG, Jiang J-k, Israelsen WJ, Keane J, Thomas C, Clish C, Vander Heiden M, Xavier RJ, O'Neill LA. Pyruvate kinase M2 regulates HIF-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab. 2015;21(1):65–80. doi: 10.1016/j.cmet.2014.12.005 Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM, Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW, Cantley LC, Thomas CJ, Vander Heiden MG. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012;8(10):839–47. Erratum in: Nat Chem Biol. 2012;8(12):1008. Walsh MJ, Brimacombe KR, Anastasiou D, Yu Y, Israelsen WJ, Hong BS, Tempel W, Dimov S, Veith H, Yang H, Kung C, Yen KE, Dang L, Salituro F, Auld DS, Park HW, Vander Heiden MG, Thomas CJ, Shen M, Boxer MB. ML265: A potent PKM2 activator induces tetramerization and reduces tumor formation and size in a mouse xenograft model. Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information; 2012 Mar 16 [updated 2013 May 8]. Public Health Impact One strategy to target cancer cells is to take advantage of their altered metabolic profiles, which distinguish them from other healthy cells. Developing a PKM2 activator allows scientists to intervene at a crucial crossroad of cancer metabolism, allowing for the selective and efficient killing of cancer cells. The development of such bioactive agent may lead to the discovery of a new effective, albeit less toxic, chemotherapeutic regimen. | Development of an Activator of the Pyruvate Kinase Isoform M2 (PKM2) | Development of an Activator of the Pyruvate Kinase Isoform M2 (PKM2) | ||||||
| 9335 | Development of a Small Molecule Inhibitor of the O-Linked β-N-Acetylglucosamine Transferase (OGT) | Scientific Synopsis OGT is a central enzyme involved in the post-translational modifications of proteins; it catalyzes the transfer of N-acetylglucosamine (GlcNAc) from uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to the serine and threonine residues of nucleocytoplasmic proteins. This post-translational modification has been implicated in gene transcription, stress response and nutrient sensing. The activity of OGT is tightly linked to the metabolic status of cells. Dysregulated O-GlcNAcylation has been linked to cancer, diabetic complications and other pathologies. To better understand the various functions of OGT in transcriptional, signaling and metabolic pathways, the project team sought to design a small molecule inhibitor of OGT. Using the NCATS qualitative high-throughput platform and following iterative rounds of structure-activity relationship (SAR) studies, the team developed OSMI-1, a cell-permeable small molecule inhibitor of OGT. Further medicinal chemistry efforts are currently underway to improve the activity and pharmacologic profile of our OGT inhibitors. The scheme on the left illustrates how OSMI-1 inhibits the ability of OGT to catalyze the transfer of GlcNAc from UDP-GlcNAc to the serine and threonine residues of proteins. The Western blot gels on the right show that incubation with OSMI-1 drastically reduces the N-acetylglucosylation of proteins in the cell. (Reprinted with permission from Ortiz-Meoz R, et al. A small molecule that inhibits OGT activity in cells. ACS Chem Biol. 2015;10(6):1392–7. Copyright 2015 American Chemical Society. Lead Collaborators Craig J. Thomas, Ph.D.,NCATS, NIH Damien Y. Duveau, Ph.D., NCATS, NIH Suzanne Walker, Ph.D., Harvard University Publications Ortiz-Meoz RF, Jiang J, Lazarus MB, Orman M, Janetzko J, Fan C, Duveau DY, Tan ZW, Thomas CJ, Walker S. A small molecule that inhibits OGT activity in cells. ACS Chem Biol. 2015 Jun 19;10(6):1392–7. doi: 10.1021/acschembio.5b00004 Itkonen HM, Gorad SS, Duveau DY, Martin SE, Barkovskaya A, Bathen TF, Moestue SA, Mills IG. Inhibition of O-GlcNAc transferase activity reprograms prostate cancer cell metabolism. Oncotarget. 2016 Mar 15;7(11):12464–76. doi: 10.18632/oncotarget.7039 Public Health Impact The OGT enzyme plays diverse roles in mammalian cell biology. To better understand the precise roles of OGT in cell function and disease states, targeted OGT inhibitors are needed. The goal is to develop and optimize such an inhibitor. | Development of a Small Molecule Inhibitor | Development of a Small Molecule Inhibitor | ||||||
| 9334 | Development of a Novel Inhibitor of Fumarate Hydratase in Mycobacterium Tuberculosis | M. tuberculosis is the bacterial strain responsible for tuberculosis, an infectious disease that cases more than 1 million deaths worldwide every year. The development of new pharmaceuticals to treat tuberculosis, especially pharmaceuticals with new mechanisms of action, is of increasing concern as new drug-resistant strains of tuberculosis emerge. Scientific Synopsis Fumarate hydratase is a key metabolic enzyme in both bacteria and humans, as an essential part of the citric acid cycle. Researchers at NCATS used a high-throughput chemical screen of more than 400,000 small molecules to discover a unique molecule, compound 7, which effectively inhibited fumarate hydratase. While the fumarate hydratase is a common enzyme in both humans and M. tuberculosis, with a very similar structure, compound 7 inhibits only the bacterial version of fumarate hydratase. Follow-up experiments revealed that compound 7 was acting as a dimeric inhibitor in an allosteric pocket of fumarate hydratase. To act as an effective catalyst, the C subunit of fumarate hydratase needs to close and bind to the L-malate substrate. Compound 7 effectively keeps the enzyme in the open conformation by binding between the A and C subunits. Compound 7 was then found to inhibit the growth of M. tuberculosis, but relatively high concentrations were necessary. This remains a promising lead for the development of therapeutics to treat tuberculosis. This figure demonstrates how compound 7 binds between subunits A and C of the fumarate hydratase enzyme, keeping it in the “open” conformation and making it unable to work effectively as an enzyme. (Reprinted with permission from Kasbekar M, et al. Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site Proc Natl Acad Sci USA. 2016;113(27):7503–8. Copyright 2016 Proceedings of the National Academy of Sciences of the United States of America) The crystal structure for the fumarate hydratase enzyme, with L-malate bound in the active site of the enzyme. (Reprinted with permission from Kasbekar M, et al. Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site Proc Natl Acad Sci USA. 2016;113(27):7503–8. Copyright 2016 Proceedings of the National Academy of Sciences of the United States of America) Lead Collaborators Clifton Barry III, Ph.D., National Institute of Allergy and Infectious Diseases, NIH Chris Abell, Ph.D., University of Cambridge Publication Kasbekar M, Fischer G, Mott BT. Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site. Proc Natl Acad Sci USA. 2016;113(27):7503–8. Outcomes A novel small molecule inhibitor of fumarate hydrolase with specificity for M. tuberculosis has been discovered. Future work may lead to novel treatments of tuberculosis. (Also see https://https://www.ncbi.nlm.nih.gov/pubmed/27325754 and https://ncats.nih.gov/pubs/features/oxcam-scholars) Public Health Impact Tuberculosis is a disease of serious concern, responsible for more than a million deaths worldwide every year, with antibiotic-resistant strains of tuberculosis becoming increasingly problematic. The discovery of new potential inhibitors specific to M. tuberculosis may allow for the discovery of new treatments for tuberculosis, ultimately saving thousands of lives. | Development of a Novel Inhibitor of Fumarate | Development of a Novel Inhibitor of Fumarate | ||||||
| 9326 | NCATS, Karolinska Institutet Scientists Attack Cancer’s Defenses | February 24, 2018Scientists from NCATS and Sweden’s Karolinska Institutet have developed a potential new approach to fighting cancer by breaking down a defense system used by cancer cells.Scientists from NCATS and Sweden’s Karolinska Institutet identified a compound, TRi-1, that can kill cancer cells and reduce tumor growth. The top two rows of images show tumors treated with a different compound that has no effect at the beginning of treatment (top) and at day three (bottom). The lower two rows show tumors treated with TRi-1, again at the beginning of treatment (top) and at day three (bottom). The images in the bottom row reflect the compound’s effects on reducing tumors. (Reprinted with permission from Stafford et al., Sci. Transl. Med 10, eaaf7444 (2018).)The defense system involves an enzyme, thioredoxin reductase 1 (TrxR1), which supports cancer cell survival. The research team identified a compound, TRi-1, that stops the activity of the enzyme without causing unwanted side effects, which can be common with existing chemotherapy drugs.When applied to breast and head and neck cancers in mice, TRi-1 killed cancer cells and reduced tumor growth, yet appeared to leave healthy cells and tissues alone. These results, reported Feb. 14, 2018, in Science Translational Medicine, suggest that interfering with cancer cells’ ability to protect themselves could be a useful strategy against many types of cancer.“There haven’t been any drugs specifically designed to target TrxR1,” said study co-author Anton Simeonov, Ph.D., NCATS scientific director. “These findings provide the first evidence of promising starting points to develop cancer drugs that work against only this enzyme.”Some existing thioredoxin reductase inhibitors are used to treat diseases such as rheumatoid arthritis and leukemia, and other inhibitors are in clinical testing for other disorders, but no drugs currently on the market target this enzyme as specifically as the new compound doesIn 2010, co-author Elias Arnér, M.D., Ph.D., professor of biochemistry at Karolinska Institutet, approached Simeonov and his NIH team to collaborate in developing inhibitors against the enzyme, which Arnér had been studying for more than a decade.The team needed to find specific compounds against TrxR1 that didn’t cause side effects. The researchers evaluated nearly 400,000 compounds, testing various amounts for their effectiveness in blocking enzyme activity. NCATS provided access to the compound library and the expertise and technology to screen the large number of compounds, in addition to expertise in developing needed assays (tests) and expertise in medicinal chemistry to determine the most likely kinds of molecules that could block the enzyme alone. This allowed the researchers to identify candidate compounds and — through further testing and refining — move them along the translational path to determine which were most effective against cancer cells and in animal models of cancer.“To avoid damaging normal cells, we had to ensure the compounds didn’t also inhibit another enzyme found in cells, which is similar in structure to TrxR1,” Simeonov said. “This was a key test we ran first at NCATS and later at Karolinska Institutet to select the most promising molecules that showed more specific activity against TrxR1.”Through another series of tests and analyses, the scientists narrowed the list to 53 candidate compounds — including those that worked against TrxR1 and molecules with similar structures — and evaluated their potential as drugs. When the team studied these compounds for activity against cancer cells and in enzyme activity assays, two inhibitors — TRi-1 and TRi-2 — stood out.The researchers examined the effects of TRi-1 and TRi-2 against TrxR1 in about 60 different cancer cell lines, and TRi-1 proved to be the most specific in blocking enzyme activity. The type of cancer did not seem to matter. In tests with mice, Arnér and his Karolinska Institutet colleagues showed that TRi-1 was also more effective than other candidate compounds in killing cancer cells and reducing tumor growth.Although more testing of TRi-1 and similar compounds is needed in the laboratory and eventually in cancer patients to demonstrate safety and effectiveness, the published results suggest that TrxR1 inhibitors will likely be most effective when combined with other cancer therapies.“These results are very promising because they raise the possibility of developing newer and hopefully more effective therapies for cancer patients,” Arnér said. | Scientists from NCATS and Sweden’s Karolinska Institutet have developed a potential new approach to fighting cancer by breaking down a defense system used by cancer cells. | /sites/default/files/anticancer_1260x630.jpg | NCATS, Karolinska Institutet Scientists Attack Cancer’s Defenses | Scientists from NCATS and Sweden’s Karolinska Institutet have developed a potential new approach to fighting cancer by breaking down a defense system used by cancer cells. | /sites/default/files/anticancer_1260x630.jpg | NCATS, Karolinska Institutet Scientists Attack Cancer’s Defenses | ||
| 9275 | Rare Disease Patients and Families Find Hope in Research | Translational Science Highlight NCATS supports rare disease patients and their communities by providing translational research funding, tools and other resources that are helping to address their unique challenges. After a long day of school and homework, many kids look forward to relaxed playtime. This is far from reality for Ella Murray, whose after-school activities often include a three-hour routine to take care of the wounds covering her body. In the evening, Ella’s parents must carefully remove her bandages, bathe her and break any blisters before re-bandaging her for bed. Ella was born with dystrophic epidermolysis bullosa (EB), a rare genetic condition that prevents her body from making a protein that helps hold skin together. Children with EB are sometimes called “butterfly children” because their skin is as fragile as a butterfly’s wings. Even the slightest friction can cause their skin to blister or tear. EB affects almost every organ in the body, as well as scarring in the throat and digestive tract, and in severe cases like Ella’s, a person’s fingers begin to fuse together, making it difficult to use their hands. Joe Murray with his daughter Ella. “Rare diseases affect an estimated 25 million Americans and are devastating for patients, their families and the nation as a whole,” said Petra Kaufmann, M.D., M.Sc., director of NCATS’ Office of Rare Diseases Research (ORDR). “Most of these disorders are serious or life-threatening, chronic, progressive, inherited — otherwise known as genetic — disorders.” To help create more awareness, each year since 2009, NCATS and the NIH Clinical Center have co-sponsored Rare Disease Day at NIH. This event brings patients and their families together with researchers and policymakers to learn about the latest in rare diseases research, share patients’ perspectives, discuss issues important to the rare diseases community, and share new resources. While attending the 2016 Rare Disease Day at NIH, Ella’s father, Joe Murray, shared details of his family’s story in an NCATS video project. “It fills me with great hope to know the NIH and its collaborators are fighting with their resource dollars and expertise to make the world a better place,” Murray said. Murray credits the NCATS video with spreading awareness about EB and the work of the Dystrophic Epidermolysis Bullosa Research Association of America (debra of America), where he serves as director of government and legal affairs. In May 2017, Ella was profiled in The Washington Post. It was through debra of America that Murray met Brett Kopelan, whose story very much mirrors his own. Kopelan’s daughter Rafaella, who goes by “Rafi,” was born with EB the same year as Ella. And like Ella’s days, Rafi’s include grueling and painful bandage changes and a struggle to get the calories needed to help her body heal itself and grow. “It’s exhausting,” Kopelan said. “She is certainly a lot stronger than I am.” Accelerating Progress for Rare Diseases Research Brett, Rafi and Jackie Kopelan show off the strength in partnering with patients and families for smarter science (2017). Kopelan recalls the moment when he learned why his daughter was born without skin on her feet and one hand. After hearing the diagnosis, he searched the internet for answers, only to learn that EB has no approved treatments. Research on the disease was in very early stages, and patients usually did not live past early adulthood. “This is the worst disease I’ve never heard of,” Kopelan thought at the time. He set out to help speed EB research by getting involved with debra of America, and in 2011, he became the organization’s executive director. debra of America helps families in many ways, from providing an on-call nurse for questions and support to providing specialized bandages, which are expensive and often not covered by insurance. In addition, the organization funds research on EB treatments and holds conferences to foster collaboration and speed progress. NCATS provided support for debra of America’s research conference in 2015. “Bringing together researchers from around the world with industry enables better protocol development, better recruitment — in essence, better drug development,” Kopelan said. NCATS regularly partners with patient advocacy groups to accelerate progress in rare diseases research. Through these collaborations, NCATS has developed tools, resources and other initiatives featured in the Center’s latest video, which highlights the Genetic and Rare Diseases Information Center, Toolkit for Patient-Focused Therapy Development, and more. Patients as Partners Numerous clinical trials are ongoing for EB therapies ranging from wound creams to gene therapy to stem cell transplants. But there is still significant work to do for EB and the thousands of other rare diseases that have no approved therapy. Ella Murray, Ava Navarro and Rafi Kopelan pose for the press at a debra of America event (2017). Rafi is not sitting idly by waiting for a treatment. She learned to advocate at an early age, appearing on television and in commercials to promote EB awareness. She has spoken to everyone from the senior leadership of bandage companies to biotechnology companies to classes of medical students. All her public speaking practice paid off in her successful bid for student council in 2016. As Rafi’s story demonstrates, patients play a significant role in raising awareness about rare diseases and uniting both the patient community and investigators for more efficient progress. A central part of NCATS’ mission is to partner with patients at every step of the translational research process and ensure that outcomes are relevant to and directly address patient needs. “No one patient group can solve all the challenges in rare diseases research,” Kaufmann said. “By looking for commonalities among rare diseases and finding solutions for common bottlenecks in the translational research pipeline, we hope to speed treatments for families like the Kopelans and Murrays, as well as all patients who suffer from these devastating disorders.” Posted February 2018 | Rare Disease Patients and Families Find Hope in Research | Rare Disease Patients and Families Find Hope in Research | ||||||
| 9197 | NCATS Program-Specific Funding Information | View program-specific funding information or learn more about funded projects. A Specialized Platform for Innovative Research Exploration (ASPIRE) ASPIRE Funding Information Biomedical Data Translator (Translator) Translator Funding Information Clinical and Translational Science Awards (CTSA) Program CTSA Program Funding Information CTSA Program Projects & Initiatives Extracellular RNA Communication (ExRNA) ExRNA Communication Funding Information ExRNA Communication Projects National COVID Cohort Collaborative (N3C) National COVID Cohort Collaborative Funding NCATS' Role in The Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative® NIH HEAL Initiative Funding, Prize & Collaboration Information NCATS-Supported NIH HEAL Initiative Projects Rare Diseases Clinical Research Network (RDCRN) RDCRN Funding Information RDCRN Consortia Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) SBIR & STTR Small Business Funding Information Tissue Chip for Drug Screening (Tissue Chip) Tissue Chip Funding Information Tissue Chip Initiatives & Projects | View program-specific funding information or learn more about funded projects. | /sites/default/files/ogmsr-conference.jpg | NCATS Program-Specific Funding Information | View program-specific funding information or learn more about funded projects. | /sites/default/files/ogmsr-conference.jpg | NCATS Program-Specific Funding Information | ||
| 9196 | Somatic Cell Genome Editing (NIH Common Fund Programs) | We are leading the NIH-wide working group to manage the SCGE program.Somatic Cell Genome EditingThe human genome has thousands of genes, each of which has the information that cells use to make protein. The human body needs a vast number of specific proteins to work properly. In genetic diseases, a gene has a problem that means a protein is made wrong — or not made at all. Genome editing changes the DNA sequence so that the cells can correctly make proteins again. Progress in genome editing could help treat thousands of genetic diseases.In the past decade, researchers have advanced genome editing technology to allow precise changes to the DNA code inside live cells. Using this technology, scientists could edit disease-causing DNA within the body’s non-reproductive cells, known as somatic cells. Making this technology more efficient and limiting the edits to these cells lowers the risk of having unintended editing-related changes passed down to future generations. Researchers could use this technology to potentially treat many genetic diseases.In January 2018, the NIH Common Fund launched a new program focusing on somatic cell research. The first phase of the Somatic Cell Genome Editing (SCGE) program aims to create high-quality tools for safe and effective genome editing in humans and to make these tools widely available to the research community to reduce the time and cost of creating new therapies. NCATS led the NIH-wide working group composed of staff from several other NIH institutes and centers that managed the new program. The joint program aims to:Expand the number of genome editing tools availableCreate delivery systems that can efficiently target the cells of specific organs and tissues in the human bodyDesign new assays for testing the safety and effectiveness of genome editing and delivery toolsShare the knowledge, methods and tools developed through this program with the scientific community through the SCGE ToolkitBuilding on the success of Phase 1, the next phase of the SCGE program launches in 2023. The goal of Phase 2 is to speed the translation of genome editing therapies into the clinic. NCATS and the National Institute of Neurological Disorders and Stroke will lead another NIH-wide working group to:Advance the evaluation and clinical development of novel genome editing therapiesCreate regulatory pathways to the clinic for multiple diseases at a timeShare successful strategies to start in vivo genome editing studies in humansDevelop targeted delivery technologies through the TARGETED Challenge | NCATS is leading trans-agency efforts for NIH’s new Somatic Cell Gene Editing program that aims to develop tools for safe and effective genome editing in human patients. | /sites/default/files/somatic_1260x630.jpg | Somatic Cell Genome Editing Program | NCATS is leading trans-agency efforts for NIH’s new Somatic Cell Gene Editing program that aims to develop tools for safe and effective genome editing in human patients. | /sites/default/files/somatic_1260x630.jpg | Somatic Cell Genome Editing Program | ||
| 9195 | Conference Grant Information | Investigators may apply for NIH-funded scientific conference grants to support high-quality national and international meetings that are relevant to public health and the NCATS mission. Areas of Interest Application Procedures Funding Information Conference Grant Resources Areas of Interest NCATS supports scientific meetings, conferences and workshops that are consistent with its mission of advancing translational sciences through development, improvement or innovation in cross-cutting or generalizable approaches to drug development or basic, translational or clinical scientific research. Applicants are encouraged to review the NIH guidelines to enhance diversity in conferences supported by the NIH. Applicants may submit conference grant applications for any disease or therapeutic area (or combination of areas), as long as the knowledge gained will be more broadly applicable to other areas of investigation. Examples include: Novel biologics technologies for better treatments of human disease Building multidisciplinary networks to drive science and translation NCATS also supports scientific meetings, conferences and workshops for rare diseases. As mandated in the Rare Diseases Act of 2002, the NCATS Division of Rare Diseases Research Innovation supports scientific workshops and symposia to identify research opportunities for rare diseases. Specifically, NCATS seeks applications for conferences, meetings and workshops that: Include the active participation of relevant patient support groups in the meeting planning Leverage recent breakthroughs in research or support the advancement of new research endeavors Set clinical practice or guidelines Conference grant applications that buttress the CTSA Program goals (listed on the CTSA Program in Action page) will be considered for support by the CTSA Program. Application Procedures NCATS requires that interested applicants send a letter seeking approval before submitting a conference grant application. This applies to both new and resubmitted applications. NCATS can only award conference grants prior to the meeting date. Therefore, potential applicants must choose an application receipt date from the following table that allows for an award prior to the conference: Request-to-Submit Date Application Receipt Date Scientific Merit Review Advisory Council Review Earliest Conference Meeting Start Date March 1 April 12 June/July October December 1 July 1 August 12 October/November January March 1 November 1 December 12 February/March May July 1 Obtaining Approval to Submit an Application At least six weeks before the application submission date, applicants must obtain approval from NCATS before submitting a conference grant (R13/U13) application. How to Request Approval Request-to-submit letters should be sent by e-mail to the NCATS Referral Office and include the following information: Meeting title Meeting dates and location Name and address (including e-mail) of the principal investigator Name of the sponsoring institution Brief description of the meeting’s purpose, intended audience and relevance to NCATS’ mission Draft meeting agenda, including names and affiliations of invited and/or confirmed speakers Nature of and participation by junior, minority and/or female investigators, if any List of similar meetings (recent or upcoming), if any Requested conference budget and intended use for the funds, including: Total budget Portion requested from NCATS Portion requested from other NIH Institutes and Centers, if any Intended receipt date for application submission (i.e., April 12, August 12 or December 12) NCATS usually provides a decision on the conference grant request within two weeks of receiving the Request-to-Submit letter. If accepted, NCATS will send an approval letter to the applicant via e‑mail. (Please note that NCATS’ agreement to accept an application does not guarantee funding.) Submitting an Application At the time of application submission, a copy of the approval letter must be included in the application as part of the cover letter component. Conference grant applications must be submitted electronically through grants.gov. Refer to the current funding opportunity for application and submission information. Funding Information Typically, NCATS provides between $3,000 and $25,000 per meeting, but the actual award is contingent upon availability of funds, programmatic priorities and recommendations by peer review and program staff. For applications in which NCATS is listed as the secondary NIH Institute, Center or Office (ICO), NCATS may provide the minimum of $3,000 in support. In general, NCATS does not provide co-funding support in excess of the contribution made by the primary awarding NIH ICO. While all allowable costs will be considered, NCATS places an emphasis on the support for trainees, students, fellows and young investigators for conference attendance, poster presentations and meeting participation. Diversity representation among invited speakers is also encouraged. Additionally, NCATS will consider the number of times a conference has been previously supported in making funding decisions. Conference Grant Resources For more information on the conference grant (R13/U13) mechanism, prospective applicants should review the following resources: NIH Support for Conferences and Scientific Meetings (Parent R13) NIH Support for Conferences and Scientific Meetings (Parent R13 Clinical Trial Not Allowed) NIH Support for Scientific Conferences (R13 and U13) NIH Frequently Asked Questions for Conference Grants NIH Support for Conferences and Scientific Meetings (Parent R13) — Contact and Special Interests | /sites/default/files/ogmsr-conference.jpg | Conference Grant Information | Investigators may apply for NIH-funded scientific conference grants to support high-quality national and international meetings that are relevant to public health and the NCATS mission. | Investigators may apply for NIH-funded scientific conference grants to support high-quality national and international meetings that are relevant to public health and the NCATS mission. | /sites/default/files/ogmsr-conference.jpg | Conference Grant Information | ||
| 9158 | Assay Guidance Workshop Agenda — March 26-27, 2018 | March 26, 2018 — 7:30 a.m. - 5:00 p.m. ET William F. Bolger Center, 9600 Newbridge Drive, Potomac, MD 20854 7:30 a.m.: Registration 8:00 a.m.: Robust Assays Define Success in Preclinical Research Nathan P. Coussens, Ph.D., NCATS, NIH 8:15 a.m.: Target Validation in Physiologically Relevant Drug Discovery Models Madhu Lal-Nag, Ph.D., NCATS, NIH 9:00 a.m.: Concepts in the Development and Validation of Robust Cell-Based and Biochemical Assays Timothy L. Foley, Ph.D., Pfizer Inc. 9:45 a.m.: Beverage Break 10:00 a.m.:Treating Cells as Reagents to Design Reproducible Screening Assays Terry Riss, Ph.D., Promega Corporation 10:45 a.m.: Assay Development for High-Content Screening O. Joseph Trask, Jr., PerkinElmer, Inc. 11:30 a.m.: Remarks from the Director of NCATS Christopher P. Austin, M.D., NCATS, NIH 11:45 a.m.: Lunch 1:00 p.m.: Introduction to Mass Spectrometry for Drug Screening and Lead Optimization Kenneth D. Roth, Ph.D., Eli Lilly and Company 1:45 p.m.: Assay Interference by Chemical Reactivity Jayme L. Dahlin, M.D., Ph.D., Brigham and Women’s Hospital 2:30 p.m.: Lead Selection and Optimization by Medicinal Chemistry Samarjit Patnaik, Ph.D., NCATS, NIH 3:15 p.m.: Beverage Break 3:30 p.m.: In Vitro Toxicological Testing Using a qHTS Platform Menghang Xia, Ph.D., NCATS, NIH 4:15 p.m.: In Vitro Assessments of ADME Properties of Lead Compounds Xin Xu, Ph.D., NCATS, NIH 5:00 p.m.: Adjourn March 27, 2018 — 7:30 a.m. - 5:00 p.m. ET NCATS, 9800 Medical Center Drive, Rockville, Maryland 20850 7:30 a.m.: Registration 8:00 a.m.: Statistical Design of Experiments for Assay Development Steven D. Kahl, Eli Lilly and Company 8:45 a.m.: The Application of Pharos for Target Evaluation and Drug Discovery Rajarshi Guha, Ph.D., NCATS, NIH 9:30 a.m.: Basic Assay Statistics, Data Analysis and Rules of Thumb Thomas D.Y. Chung, Ph.D., Sanford Burnham Prebys Medical Discovery Institute 10:15 a.m.: Beverage Break 10:30 a.m.: Reproducibility and Differentiability of Compound Potency Results from Screening Assays in Drug Discovery Viswanath Devanarayan, Ph.D., Charles River Laboratories 11:15 a.m.: Assay Operations: Keeping Your Assays Robust and Reproducible Jeffrey R. Weidner, Ph.D., QualSci Consulting, LLC 12:00 p.m.: Thoughts and Perspective Anton Simeonov Ph.D., NCATS, NIH 12:15 p.m.: Lunch 1:45 p.m.: Hands-On Data Analysis Sessions 5:00 p.m.: Adjourn | Assay Guidance Workshop Agenda — March 26-27, 2018 | Assay Guidance Workshop Agenda — March 26-27, 2018 |
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