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| 13834 | NCATS Releases Updated Translational Road Maps | February 15, 2019 (updated April 19, 2022)NCATS has released an expanded, interactive version of the Drug Discovery, Development and Deployment Maps (4DM) and is requesting user feedback as the Center continues development of these tools. NCATS created the 4DM to provide a common framework for discussing the therapeutic development process and identifying areas that are ripe for innovation.The original maps — released in late 2017 in both Nature Reviews Drug Discovery and Clinical and Translational Science — were static images. The latest release provides a more dynamic map interface for enhanced usability and an interactive experience. Users can zoom into and out of areas of the process to view different levels of complexity, find information and best practices, and connect to relevant NCATS programs and resources. Like the static versions, the dynamic 4DM are shareable under a Creative Commons Attribution-ShareAlike International 4.0 (CC BY-SA 4.0) license.In April 2022, the 4DM website was taken offline. | An expanded, interactive beta version of the Drug Discovery, Development and Deployment Maps provides a more dynamic map interface for enhanced usability compared with the static version. | /sites/default/files/4dmap_1260x630.jpg | NCATS Releases Updated Translational Road Maps | An expanded, interactive beta version of the Drug Discovery, Development and Deployment Maps provides a more dynamic map interface for enhanced usability compared with the static version. | /sites/default/files/4dmap_1260x630.jpg | NCATS Releases Updated Translational Road Maps | ||
| 13813 | NCATS-Supported Researchers Find Cell Source Matters for Tissue Chips | February 2, 2019Tissue chips — 3-D models designed to mimic human organs — hold immense promise to improve drug testing and development. Yet, as with many new technologies, there’s much to prove before they are widely accepted by researchers and industry.Texas A&M University researchers Arum Han, Ph.D. (left), and Ivan Rusyn, M.D., Ph.D. (right), studied the ability of a tissue chip to mimic a working human kidney. (Tim Stephenson, CVM Communications/Texas A&M University Photo)To address some of the concerns, NCATS established Tissue Chip Testing Centers (TCTCs) to independently test and validate tissue chip systems. TCTC scientists aim to evaluate how well such systems work, whether they are reliable, and whether they can be reproduced, with a goal of helping them become more available. Recently, investigators at a TCTC at Texas A&M University evaluated a kidney tissue chip model developed by researchers at the University of Washington (UW) and at the company Nortis Bio.Using kidney cells from new patients at UW and from a commercial vendor, the Texas researchers repeated many of the same experiments and tests previously performed by the UW-Nortis team. As published in Scientific Reports, cells in the Texas A&M study generally behaved similarly to those in the original UW-Nortis experiments, developing into kidney-like structures (in this case, kidney tubules) and performing the same functions as real kidneys.The scientists also found that the source of kidney cells mattered. There were enough differences in the original study, including in cells’ abilities to metabolize vitamin D and generate ammonia, that the scientists recommended using a commercially available source of cells, including stem cells when possible. Many tissue chip systems already employ induced pluripotent stem cells, which can develop into any type of cell and are a renewable resource.The researchers also examined several cancer chemotherapy drugs known to be toxic to kidneys, demonstrating the tissue chip model’s usefulness in evaluating drug toxicity.“The testing centers’ main goal is to bridge the gap between the development of technologies and their actual use in industry to solve real-world problems in drug testing and disease modeling,” said Ivan Rusyn, M.D., Ph.D., Texas A&M toxicologist. “We’re working to provide realistic expectations for using the models.” | Researchers from the Tissue Chip Testing Center at Texas A&M University have evaluated a kidney-on-a-chip’s ability to perform the same functions as real kidneys. | /sites/default/files/tctc-rusyn_1260x630.jpg | NCATS-Supported Researchers Find Cell Source Matters for Tissue Chips | Researchers from the Tissue Chip Testing Center at Texas A&M University have evaluated a kidney-on-a-chip’s ability to perform the same functions as real kidneys. | /sites/default/files/tctc-rusyn_1260x630.jpg | NCATS-Supported Researchers Find Cell Source Matters for Tissue Chips | ||
| 13804 | Proposal to Collaborate Instructions | OverviewThis is not a grant application — if successful, funds will not be transferred to your institution to support your project. Instead, this is an application to collaborate with and gain access to the scientific capabilities, expertise and resources of the NCATS Division of Preclinical Innovation (DPI), with the goal of developing novel testing platforms or developing promising probes for pain, addiction or overdose indications. If successful, you will partner with DPI staff in developing a collaborative project plan. DPI will provide translational expertise and operations, and the applicant investigator collaborator(s) will provide starting points for the project and biological/disease expertise.General InformationPre-proposals and proposals will be accepted and reviewed on a rolling basis. • Pre-proposals are requested to maximize efficiency of effort from collaborators and NCATS, ensuring candidate projects are within the scope of the National Institutes of Health (NIH) Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, and the capacities of the NCATS DPI. Successful pre-proposal applicants will be asked to submit a full proposal. Upon approval of the pre-proposal, additional information to be included in the full proposal will be required, depending on which component of the Human Cell-Based Screening (HCBS) program is being applied to for collaboration (iPSC-Derived Cell-Based Model Development or Pharmacological Probe Development). Program staff will help direct applicants to the most relevant program component.• Pre-proposals can be submitted at any time to NCATSDPIHEALCollab@nih.gov.• No full proposals will be accepted if they were not invited in response to a pre-proposal.• Applicants whose full proposals are accepted will enter into discussions with NCATS scientists to explore possible implementation and make a final determination of whether to develop a collaboration plan. Factors that will be considered in this decision include feasibility, alignment of goals, potential milestones and go/no-go decisions. Only after a collaboration plan is agreed to by both partners will the project officially begin.• Organizations eligible to submit collaboration proposals include: o Public/state-controlled institution of higher education o Private institution of higher education o Nonprofit with 501(c)(3) IRS status (other than institution of higher education) o Nonprofit without 501(c)(3) IRS status (other than institution of higher education) o Small business o Eligible agencies of the federal government, including NIH intramural laboratories• Submission requirements: o Potential collaborators are advised to submit only one proposal at a time. o Resubmissions are allowed only if substantially improved. Pre-Proposal Submission Process• Pre-proposals are limited to two pages, 11-point Calibri font; material beyond the two-page limit will not be considered.• Pre-proposals must be submitted by email to NCATSDPIHEALcollab@nih.gov.• Pre-proposals must use the following structure: o Proposal title o Name, affiliation and expertise of lead collaborator o Primary component of the Human Cell-Based Screening (HCBS) program being applied to (choose one): • iPSC-Derived Cell-Based Model Development • Pharmacological Probe Development o Detailed description of the current state/starting point for proposed collaboration o Goal/desired deliverable from proposed collaboration o Novelty of approach/desired deliverable. If similar models, probes or drugs currently exist or are in development, explain why your approach is different and better. o Statement of how success on the proposed project would impact the opioid crisis and advance the goals of the HCBS initiative o NOTE: Any intellectual property (IP) generated before initiation of the NCATS collaboration will be retained by the investigator/institution as background IP. The potential for development of new IP will depend on the stage at which the project enters into collaboration with NCATS. However, all collaborators should anticipate that there may be joint IP development with NCATS employees. Inventorship of any new, multi-party IP created from this collaboration will be determined according to U.S. patent law and governed under an agreement that will be executed at the outset of the formal research partnership, such as a Cooperative Research and Development Agreement (CRADA) or a Research Collaboration Agreement (RCA). Applicants are encouraged to review the templates for CRADAs and RCAs and talk with their respective technology transfer office prior to submitting a collaboration proposal, to ensure that they will have the freedom to enter into an agreement with NCATS. The templates can be found at the Forms & Model Agreements page. Questions regarding these NCATS agreement templates can be sent to the NCATS Office of Strategic Alliances via email at NCATSPartnerships@mail.nih.gov. Full Proposal Submission ProcessPotential collaborators will use the following process to submit a full proposal.• Full proposals are limited to seven pages, 11-point Calibri font, inclusive of data tables and figures. The proposal should incorporate information from the two-page pre-proposal.• Full proposals must be submitted to the e-mail address provided with the notification to submit.• All full proposals will contain the information listed below. Upon approval of the pre-proposal, additional information to be included in the full proposal will be required depending on which component of the Human Cell-Based Screening (HCBS) program is being applied to for collaboration (iPSC-Derived Cell-Based Model Development or Pharmacological Probe Development,). o Proposal title o Name, affiliation and expertise of the lead collaborator and other key personnel o Current support for the project and resources available • Description of any unique resources (models, reagents, etc.) you will bring to the collaboration o Detailed description of the starting point and desired deliverable from the proposed collaboration, including accomplishments to date, prototypes and current roadblocks to reaching the deliverable o Detail on the novelty of the approach/desired deliverable, including prior art. If similar models, probes or drugs currently exist or are in development, explain why your approach is different and better. o Proposer’s conception of best scientific approach to reaching deliverable. • Proposed milestones, assignment of responsibilities — NCATS versus potential collaborator — and proposed timeline (note: collaborations that can be completed within 2–3 years are anticipated.) • Proposed go/no-go decision points • Next steps if the project is successful o Indication of how the desired deliverable would impact the opioid crisis and advance the goals of the NIH HEAL Initiative• Supplemental Information o Summary Abstract: Please provide a project abstract (500-word max) separate from the main proposal. The abstract must summarize the proposed collaboration in a way suitable for public dissemination. If applicable, describe the disease; the proposed model, assay, probe; the current state of the project (i.e., an indication of the available assay or efficacy, pharmacology and safety data); the resources required to advance development; the public health impact on the opioid epidemic; and why NCATS is the desired partner for collaboration. The abstract should be informative to other scientists working in the same or related fields and understandable to a scientifically or technically literate lay reader. Do not include proprietary, confidential information or trade secrets. o Support letters (not to exceed one page each) should be a commitment of support, not merely an endorsement • From additional collaborators who will be contributing to the project • From the collaborators’ institution(s) o Description of IP (not to exceed four pages): To ensure freedom to operate on the proposed project, a clear description of the relevant patent space and status of IP is required (where relevant). This includes a list of any patents issued or pending with respect to either the agent to be developed or any non–commercially available technology or material required for the proposed project. Should a project require the use of non–commercially available technology or equipment that is patented by a third party, the collaborator should be prepared to explain how these materials will be accessed for this proposed collaboration. The following information is REQUIRED for the full proposal. If any of the following are not applicable to the project, state that explicitly (e.g., “There is no IP filed for the technology to be used for this project”). • Details of any existing IP at the collaborating institution that will be used in the project • Patents and patent applications • Significant know-how • Details of any third-party obligations regarding the relevant IP o Reference List • No more than 15 references relating directly to the proposal o Key Papers • PDFs of key papers that provide critical data may be included o Biosketches for All Key Personnel • Each biosketch should be no more than three pages and include the qualifications of key personnel, how they will contribute to the collaboration, verification of their ability to commit the time anticipated to complete the proposed work, and track record of collaboration. o Protection of Human Subjects (if applicable) Input From Technical ExpertsProjects will be evaluated by ad-hoc technical experts with the necessary technical and subject matter expertise. Input from technical experts is a privileged communication with NIH and may involve trade secrets, as well as commercial and financial information that is considered business confidential information.• Areas for Input: Technical experts will not provide a score but rather will provide input on the strengths and weaknesses of the proposal, using the questions below to structure their review. Because this is a proposal for collaboration, the collaboration plan and much of the scientific approach will be determined after the project is selected. The technical review should focus on the research that has been done to date on the project, the areas proposed for collaboration, and the impact on the opioid crisis if the goals/end point of the collaboration are achieved, as well as the potential for the project to progress after the collaboration has ended. In general, collaborations that can be completed in 2 to 3 years are anticipated. o Technical Review Criteria • Scientific merits of the proposed collaboration • Is the premise of the project strong? • If the goals are accomplished, how will the opioid crisis be affected? • Will the work shift paradigms? • Is the work novel? • If human material is being used, is the description of human subjects protection consistent with NIH policies? • Are potential pitfalls/issues described? • Investigator(s) • Do the collaborators have the appropriate training and experience to advance the project once the collaboration has come to a close? • What is the record of accomplishment and collaboration? • Environment • If collaborators are proposed to conduct parts of the project themselves, do they have the necessary resources to accomplish their aims? • Is there evidence of institutional support? • Feasibility of completing goals • Will the milestones serve as strategic and objective benchmarks of progress? • Are the milestones realistic? • Synergy with HCBS goals • Translational sciences and public health impact o Experts will also note: • Specific strengths of the project • Specific weaknesses/recommendations for project improvement• Decisions about which projects to explore with the potential collaborator for possible implementation will be made by the Scientific Director and NCATS Director, based on the input of the technical experts, portfolio balance and availability of NCATS resources.• Decision Notification o The program manager will send the prospective collaborator a letter informing him/her whether the project has been accepted for consideration. Next: Collaboration Notification | Proposal to Collaborate Instructions | Proposal to Collaborate Instructions | ||||||
| 13801 | NIH HEAL Initiative Expertise and Resources | Contact: NCATSDPIHEALCollab@nih.govNCATS is offering opportunities to apply our state-of-the-art technologies and extensive experience in therapeutic development to ideas and expertise in pain, addiction and overdose through collaboration. Open opportunities for collaboration fall into two general categories: novel human cell–based screening platforms and pharmacological probe development.Novel Human Cell–Based Testing PlatformsTraditionally, discovery of small molecule probes and drugs has begun with screens in cell-free systems or cell lines with heterologously expressed genes, often of non-human origin. Although these platforms have value, they may identify compounds that do not reflect native human cellular physiology or disease, which have a high likelihood of failure at later stages of the translational process. The advent of induced pluripotent stem cell (iPSC) and 3-D tissue printing technologies offers the opportunity to develop screening platforms that more accurately reflect human disease physiology and will allow the discovery of more robust and ultimately successful probe compounds and drugs for pain, addiction and overdose.iPSC-Derived Cell-Based Model DevelopmentInvestigators with a desire to develop and characterize iPSC-derived cell types relevant to nociception (e.g., primary and associative pain pathways), addiction (e.g., reward pathways) and overdose should apply. Proposals in this space should focus on development, in-depth characterization and rigorous utilization of human iPSC–based assays related to modeling and reversing pain, addiction and opioid overdose. The NCATS Stem Cell Translation Laboratory has specialized expertise in development of robust, reproducible and scalable automated iPSC differentiation protocols and comprehensive cell characterization. Among the lab’s capabilities are:• Advanced imaging technologies (e.g., high-content confocal, calcium imaging, optogenetics) and data analysis for functional cell characterization, including longitudinal tracking of cell behaviors with multiple measurements over days, weeks or months• High-throughput electrophysiology methods (e.g., high-density multi-electrode arrays [26,400 electrodes/well]) to streamline monitoring of electrical activity at high spatiotemporal resolution• Measurement of cell signaling pathways, metabolism and specific targets (e.g., cyclic AMP, PKA activity, CREB phosphorylation, energy metabolism)• Combined single-cell transcriptomic and proteomic analyses that provide information on drug response in individual cells• Access to large numbers of iPSC-derived sensory neurons (nociceptors), neuronal subtypes (e.g., GABAergic, glutamatergic, dopaminergic) and astrocytes in chemically defined conditions already extant in the lab Pharmacological Probe DevelopmentThe first step in qualifying a novel molecular target as potentially useful in therapeutic applications is the creation of a small molecule “probe” compound that can test the therapeutic hypothesis in cell-based or animal model systems. Investigators who have identified potential pain, addiction or overdose targets can collaborate with this program to generate an optimized probe that will enable the testing of a therapeutic hypothesis. The laboratory encompasses assay development; quantitative high-throughput screening (HTS) to identify promising compounds to modulate novel targets; and optimization by medicinal chemists to optimize potency, selectivity and pharmacokinetic properties required of an in vitro/in vivo pharmacological probe of the novel target. Assays of target activity adaptable for HTS, secondary assays to guide medicinal chemistry optimization and biological validation, and animal efficacy models, when applicable, should be available in the applicant’s laboratory. Probes can also be tested using the iPSC or 3-D bioprinting platforms previously developed by NCATS. Sharing probes with the scientific community will be a priority. Capabilities include:• Adaptation/miniaturization of assays for HTS and new assay development• Large diversity screening chemical libraries and specialty libraries for mechanistic dissection and drug repurposing• Counterscreening/confirmatory assays, including for common artifactual activities• Chemical informatics• Medicinal chemistry• In vitro ADMET and in vivo DMPK characterization• HEAL target and compound library on 1,536-well and 384-well plate formats | NCATS is offering opportunities to apply our technologies and experience in therapeutic development to ideas and expertise in pain, addiction and overdose through collaboration. | HEAL Expertise and Resources | NCATS is offering opportunities to apply our technologies and experience in therapeutic development to ideas and expertise in pain, addiction and overdose through collaboration. | HEAL Expertise and Resources | ||||
| 13798 | NCATS Call for Proposals for Collaboration for the NIH HEAL Initiative | Developing Drugs and Human Cell-Based Testing Platforms for Pain, Addiction and OverdoseSafe, effective, and non-addictive drugs (small molecules and biologics) to treat pain, mitigate addiction and reverse overdose are key to addressing the opioid crisis. Given the limitations of current treatments and failures in development efforts for new therapies, drugs with better activity profiles that modulate novel targets, as well as more predictive drug development platforms, are needed. The National Institutes of Health (NIH) Helping to End Addiction Long-termSM Initiative, or NIH HEAL InitiativeSM, is a trans-NIH effort launched in April 2018 to advance national priorities in addressing the opioid crisis through science. The NCATS-led NIH HEAL Initiative Human Cell-Based Screening Platforms and Novel Drugs to Treat Pain, Addiction and Overdose (HCBS) initiative is a multi-component collaborative program that will develop human-based, physiologically relevant in vitro screening and characterization systems; high-efficiency synthesis and testing of small molecule compounds to modulate novel pain, addiction, and overdose targets; and investigational new drug (IND)-enabling studies for drugs for these indications.The NCATS Division of Preclinical Innovation (DPI), the intramural component of NCATS, comprises industry-scale expertise in stem cell biology, assay development, biomolecular screening, automated biology, medicinal chemistry, cheminformatics, data science and preclinical drug development, with advanced equipment and resources not available in most laboratories, such as large compound libraries (e.g., diverse drug-like molecules, approved and investigational drugs, mechanism-based compounds, and natural products); quantitative high-throughput and high-content screening; robotic automated cell culture; multiscale assay development; 3-D bioprinting; next-generation DNA and RNA sequencing; and integrated platforms to profile gene and protein expression and measure functional endpoints in cell cultures and on single cells.Every NCATS DPI project is a collaboration with an external partner in the academic, biopharmaceutical or nonprofit sector. DPI functions via a unique operational model, which takes advantage of the complementary nature of our translational expertise and collaborators’ biology/target/disease expertise. Collaborators bring a wealth of background knowledge and a starting point for a particular translational project, and our scientists bring an equivalent wealth of knowledge in translation and the expertise to transform those starting points into therapeutically useful tools, platforms or investigational drugs. Joint project teams design and follow milestone-driven project plans to achieve agreed-upon deliverables specific to the need and stage of the project. Projects are provided the needed resources as long as milestones and timelines continue to be met, until the deliverables are completed. At whatever stage the projects conclude, the joint teams publish results in scientific journals where appropriate and disseminate relevant data, protocols and materials.View a slide presentation on Developing Drugs and Testing Platforms for Pain, Addiction and Overdose in Collaboration with NCATS (PDF - 2.45MB).To view a presentation on how to collaborate with NCATS scientists, please go to 5:34:00 in the following video: https://videocast.nih.gov/Summary.asp?Live=31408&bhcp=1. | NCATS Call for Proposals for Collaboration for the NIH HEAL Initiative | NCATS Call for Proposals for Collaboration for the NIH HEAL Initiative | ||||||
| 13807 | Collaboration Notification | The initial notification of selection for possible implementation is to inform you that NCATS would like to explore the possibility of collaborating. Depending on the completeness of the information provided in your proposal, NCATS may request additional information before making a decision about the development of the provisional milestone-driven collaboration plan.Collaboration Plan• If the proposal is selected for possible implementation, the program manager will arrange an in-depth meeting with the collaborators. If the meeting is to be face-to-face, funding will be provided for the lead collaborator to travel to NCATS as needed.• The NCATS Division of Preclinical Innovation (DPI) collaborating lab will discuss with the selected collaborators what the needs are, discuss what the collaborator will contribute to the collaboration, and determine whether to proceed with developing a detailed collaboration plan and further refine the milestones that define the go/no-go decision points.• NCATS will notify the potential collaborator of the decision to proceed to collaboration plan development or stop.• The NCATS Office of Strategic Alliances will engage with the collaborator and the DPI lab to execute the appropriate agreements, such as Cooperative Research and Development Agreements (CRADAs) and Research Collaboration Agreements (RCAs). Test of Concept/Model System Validation• The first implementation go/no-go decision ― NCATS will determine the reproducibility of the concept and/or the model system. o Successful reproducibility will result in full study implementation. o Unsuccessful reproducibility will serve as the first no-go decision point. The program manager will set up a meeting with relevant personnel to discuss troubleshooting options. If no options are viable, the project will be closed. Project Progression• Lead collaborators and NCATS project leads will provide progress reports when milestone dates occur AND when prompted by NCATS leadership. o Go/no-go decision points will prompt project review. The National Institutes of Health (NIH) Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, lab leads will determine whether the milestones have been met and whether the project should proceed. • Missed milestones will trigger project review. The program manager will arrange a meeting with the team lead, project lead and lead collaborator to determine why the milestone was missed and possible remedial approaches or project termination. • If the recommendation is to terminate the project, the NCATS Director and Scientific Director will be consulted prior to termination. Publication of ResultsIf a proposal is accepted for collaboration, the collaborator will agree that data (positive and negative results) and resources generated under the collaboration will be shared with the public through appropriate mechanisms that respect intellectual property, including pre-print servers, peer-reviewed publications and data-sharing sites, such as PubChem, for high-throughput screening data. | The initial notification of selection for possible implementation is to inform you that NCATS would like to explore the possibility of collaborating. | Collaboration Notification | The initial notification of selection for possible implementation is to inform you that NCATS would like to explore the possibility of collaborating. | Collaboration Notification | ||||
| 13696 | NCATS-Supported Researchers Find Exercise May Help Protect DNA | June 1, 2019People who care for chronically ill family members are at high risk for stress and health problems. They are also less likely to exercise. These risk factors are linked to having shorter telomeres, the caps that protect the ends of DNA. Telomeres shorten over a person’s lifetime, and shorter telomeres are thought to contribute to age-related diseases, including cancer and cardiovascular disease.The 46 human chromosomes are shown in blue, with the telomeres appearing as white pinpoints. (National Cancer Institute Photo/Hesed Padilla-Nash and Thomas Ried)To learn more, NCATS Clinical and Translational Science Awards Program-supported researchers at the University of California, San Francisco, conducted a study of older individuals caring for family members with dementia. They sought to determine if exercising could lengthen telomeres in this high-risk group of caregivers who did not regularly exercise before the study. As published in the December 2018 issue of Psychoneuroendocrinology, they found that participants in the six-month exercise program had longer telomeres than they did at the start of the study. Those who exercised also lost weight and reported that they had less stress. Participants in the control group that did not exercise had slightly shorter telomeres after six months, an expected outcome from aging.Additional research is needed to better understand why the exercising participants’ telomeres were longer, but the results suggest there are ways to potentially lengthen telomeres in older adults, which could lead to better health outcomes as they continue to age. | CTSA Program-supported researchers who studied older caregivers found that those who exercised had longer telomeres. These findings may lead to better health outcomes for older adults as they age. | /sites/default/files/telomeres_1260x630.jpg | NCATS-Supported Researchers Find Exercise May Help Protect DNA | CTSA Program-supported researchers who studied older caregivers found that those who exercised had longer telomeres. These findings may lead to better health outcomes for older adults as they age. | /sites/default/files/telomeres_1260x630.jpg | NCATS-Supported Researchers Find Exercise May Help Protect DNA | ||
| 13708 | Rare Diseases Are Not Rare! Challenge Offers New Tools to Raise Awareness | All too often, the nearly 7,000 rare diseases are misunderstood as being hidden, obscure disorders that affect only a small number of people. In reality, one in 10 people in the U.S. — that’s about 30 million individuals — has a rare disease. About 80 percent of these diseases are genetic in origin, more than half affect children, and many are life-threatening. To address such misconceptions, in September 2018, NCATS launched a Challenge seeking creative ways to help raise awareness about rare diseases and the need for expanded research and patient support. The response was nearly 50 submissions, which included posters, videos, poems and more. Artwork from the First Place entry “Unicorns and Super Heroes Are Rare — Rare Diseases Are Not” NCATS selected 11 honorable mentions and three winners: First Place, $3,000: Nancy Netherland for “Unicorns and Super Heroes Are Rare — Rare Diseases Are Not.” Her entry incorporated designs for posters, social media posts, presentation materials and infographics depicting unicorns, superheroes and other mythical figures, combined with brief rare disease facts and humor to show how common rare diseases are. Second Place, $1,500: Christina Loccke, Lindsey Bergstrom and Sarah Theos for “In the Land of Rare Disease,” a video narrated by a child. It includes original artwork from children with rare diseases, combined with brief facts about rare diseases. Third Place, $500: Matthew Beardall, Sami Assaf and Naveen Upender for “Unicus,” a video compilation of “person-on-the-street” interviews with random community members in Bethesda, Maryland. “Unicus,” which is Latin for unique, provides rare disease education through informal conversations. NCATS will display all the entries at Rare Disease Day at NIH on Feb. 28, 2019, at NIH in Bethesda, Maryland. “The response from the rare disease community to our Challenge was overwhelming,” said Anne Pariser, M.D., director of the NCATS Office of Rare Diseases Research. “We’re trying to speak with one voice and bring attention to rare diseases generally and the need for more research and greater patient care. Patients and families, institutions, advocacy groups, rare diseases organizations, children’s hospitals, and others can use these efforts to help get the word out.” Posted January 2019 | NCATS selected winners from nearly 50 submissions to a Challenge seeking creative ways to raise awareness about rare diseases and the need for expanded research and patient support. | /sites/default/files/rdanr-poster-superheroes_1260x630px.jpg | Rare Diseases Challenge Winners | NCATS selected winners from nearly 50 submissions to a Challenge seeking creative ways to raise awareness about rare diseases and the need for expanded research and patient support. | /sites/default/files/rdanr-poster-superheroes_1260x630px_0.jpg | Rare Diseases Challenge Winners | ||
| 13906 | Antifibrotic Therapy for the Treatment of Pulmonary Hypertension | Pulmonary arterial hypertension (PAH) is a rare, progressive condition affecting the heart and lungs. It is characterized by abnormally high blood pressure (hypertension) in the pulmonary artery that carries blood from the heart to the lungs. The most common symptoms are shortness of breath during exertion and fainting spells, and as the condition worsens, patients can experience dizziness, swelling of the lower extremities, chest pain, and a racing pulse. Forms of PAH are classified based upon the underlying cause of disease, which guides treatment. However, effective treatments are lacking for patients whose condition is driven by fibrotic processes that damage the lungs. The lead collaborators identified a compound that improved the hypertension and fibrosis in animal models of PAH. The goal of this project was to optimize the compound for further preclinical development. Scientific Synopsis Relaxin was originally discovered as a hormone of pregnancy, promoting cardiovascular and renal adjustments to meet the increased nutritional demands of the growing fetus, the elevated requirements for renal clearance of metabolic wastes, and the relaxation of smooth muscle and ligaments to facilitate labor and delivery. The relaxin/insulin-like family peptide receptor 1 (RXFP1) has both antifibrotic and vasodilatory effects when stimulated by relaxin. While recombinant relaxin has been explored clinically for various diseases, its short half-life and requirement for intravenous delivery present obstacles for longer-term use. To circumvent these limitations, the lead collaborators identified a synthetic small molecule agonist of RXFP1 (ML290) as an alternative to relaxin hormone. In an animal model of chemically-induced fibrosis, ML290 was shown to reverse fibrotic damage. In a second animal model of hypoxia-conditioned PAH, ML290 was shown to reduce right ventricular systolic pressure and attenuate right ventricular hypertrophy after intraperitoneal administration. These observations supported the hypothesis that a small molecule RXFP1 agonist could be useful to treat PAH in patients with idiopathic pulmonary fibrosis. Lead Collaborator Florida International University, Miami, Florida Alexander Agoulnik, Ph.D. Public Health Impact The dual antifibrotic and vasodilatory effects of a single compound (ML290 or a derivative) represented a more comprehensive approach to treating this challenging condition. In addition to PAH, such a compound also could have wider applications for other fibrotic conditions in other organs, such as liver, skin and kidney. Outcomes TRND scientists completed a medicinal chemistry campaign to optimize ML290, identifying a series of agonists with the desired in vitro pharmacological profile and improved drug-like properties and pharmacokinetics after oral administration. However, after careful study in animal models, it became apparent that there was a disconnect between the in vitro activities of the ML290 series and the in vivo efficacy. As a result, the project was discontinued. | Antifibrotic Therapy for the Treatment of Pulmonary Hypertension | Antifibrotic Therapy for the Treatment of Pulmonary Hypertension | ||||||
| 13903 | BPN14770 for Treatment of Fragile X Syndrome | Fragile X syndrome (FXS) is one of the most common causes of mental impairment and is the most common single-gene cause of autism. The disease is caused by mutations in a gene on the X chromosome, affecting about one in 4,000 to 5,000 males and one in 6,000 to 8,000 females. Patients display a range of neuropsychiatric symptoms, including intellectual disability, delayed language acquisition, poor social interaction, hyperarousal, hypersensitivity, repetitive behaviors, disrupted sleep and attention deficit hyperactivity disorder. Current therapies include antipsychotics, antidepressants and other stimulants to manage disease symptoms, but there are no Food and Drug Administration (FDA)–approved treatments for FXS itself. The lead collaborators have identified a compound that reverses key deficits in genetic models of FXS. The goal of this project is to complete key preclinical studies to enable clinical evaluation in juvenile FXS patients. Scientific Synopsis The lead collaborators have developed a small molecule inhibitor (BPN14770) of phosphodiesterase-4D (PDE4D). In FXS, large expansions of CGG repeats within the FMR1 gene result in its silencing and subsequent loss of the encoded protein. This protein product, FMRP, plays a regulatory role in the brain, suppressing the translation of mRNA important for synaptic function. Loss of FMRP results in decreased production of cAMP, overexpression of otherwise tightly regulated genes, and synaptic dysfunction characteristic of FXS. Modulation of cAMP signaling through PDE4 inhibition had previously been tested in fruit fly models of FXS, showing an ability to rescue behavioral and structural phenotypes. The FRAXA Research Foundation tested BPN14770 in mouse models of FXS, showing increases in behavioral activity and social interaction, as well as restoration of brain cAMP levels. Lead Collaborator Tetra Discovery Partners, Inc., Grand Rapids, Michigan Mark Gurney, Ph.D., M.B.A. Public Health Impact Fragile X syndrome is a rare disorder affecting approximately 30,000 patients in the United States. There are no FDA-approved therapies for FXS, and the off-label medications commonly used to manage disease symptoms come with undesirable side effects. There is a clear unmet medical need for new therapies for FXS. Outcomes Approved studies are ongoing. Project Details Investigational New Drug (IND)-directed toxicology | BPN14770 for Treatment of Fragile X Syndrome | BPN14770 for Treatment of Fragile X Syndrome |
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