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| 281 | Development of Propofol Hemisuccinate for the Treatment of Epilepsy | Epilepsy is a brain disorder that causes repeated seizures over time. The seizures can be disabling and, due to loss of muscle control, pose the risk of injuries from falling. An estimated 2 million Americans have epilepsy. A migraine is a common type of severe headache that causes nausea, vomiting and sensitivity to light. Migraines can run in families, and they affect women more often than men. Some migraines and epilepsy are not responsive to treatments. The drug propofol, used during surgery and medical procedures to sedate patients or put them to sleep, could be effective in treating or preventing migraines and seizures. The investigators are developing an inhaler device for patients whose conditions have not responded to routine therapy. Patients can use the inhaler to breathe in propofol just before or during a migraine or seizure. Scientific Synopsis The investigators are developing an inhaler system to treat intractable epilepsy and migraine. The system has two uses in epilepsy. In the first epilepsy application, the system is used by a patient experiencing a seizure aura to prevent a full-blown (motor) seizure. In the second epilepsy application, the system is used by a caregiver or by a bystander to treat a patient with epilepsy who is experiencing status epilepticus or seizure clusters in an out-of-hospital setting. The system also may be used to treat migraine: a patient experiencing a migraine aura or early migraine attack uses the system to abort the migraine symptoms and prevent the development of a full-blown headache. The system administers a proprietary water-soluble prodrug form of propofol by nebulization into the deep lung. The investigators have conducted extensive proof-of-principle studies demonstrating that intrapulmonary propofol hemisuccinate (PHS) effectively protects against seizures in animal models. The team also has acquired preliminary data in an animal model of cortical spreading depression, supporting the use of PHS in the treatment of migraine. Finally, they have shown that intrapulmonary PHS does not cause pulmonary damage or inflammation. The investigators plan to conduct human safety and efficacy studies of nebulized PHS in normal volunteers and in persons with epilepsy who experience seizure auras prior to a full-blown motor seizure. In these early clinical trials, PHS solution will be administered with an off-the-shelf nebulizer system. At a later stage in this project, the researchers anticipate developing a custom-designed, miniaturized, portable electronic nebulizer system that can be carried easily by patients. Following the development of the portable delivery system, the team may conduct studies in the treatment of status epilepticus seizure clusters or migraine. Lead Collaborator Regents of the University of California, Oakland , California Michael Rogawski, M.D. Public Health Impact Epilepsy and migraine are neurological disorders whose therapeutic approach is commonly preventive. Treatment of acute attacks is difficult and frequently dependent on assistance by a health care professional. The proposed research seeks to develop a portable drug inhaler that can be used to stop a developing seizure or a migraine headache. Outcomes BrIDGs scientists developed and validated analytical methods for the drug substance, synthesized GMP propofol hemmisuccinte, developed a suitable formulation for dosing, and conducted pharmacology and toxicology studies. Preclinical data did not warrant filing an Investigational New Drug (IND) application, since efficacy data could not be reproduced with the non-GMP drug product. The project was closed and BrIDGs support was concluded. Project Details Manufacture of Good Manufacturing Practice (GMP) active pharmaceutical ingredient Formulation development Pharmacokinetic studies Manufacture of drug product Dose range finding toxicology | ||||||||
| 280 | Budget | As with all of NIH, the budget for NCATS is based on the fiscal year (FY) appropriation provided by Congress and the President. The process starts with the President’s Budget Request, which is usually released in February. The President's request typically is followed by appropriation hearings by Congress, which result in appropriation bills and reports. The final appropriation bill, if passed by Congress and signed by the President, provides NCATS with its budget for the FY (October 1 through September 30). NCATS tracks the status of its budget and provides relevant information below. The status of all appropriation bills also is available. Future Fiscal Year: 2024 Budget Request On March 9, 2023, the President’s Budget for FY 2024 was released. Additional supporting materials were released on March 13, 2023. The FY 2024 budget request for NIH is $48.6 billion. The FY 2024 budget request for NCATS (PDF – 3.0MB) is $923.3 million. A 2-page NCATS fact sheet (PDF - 1.3MB) is also available. Click to view/download Congressional Justification FY 2024 Click to view/download fact sheet Current Fiscal Year: 2023 Appropriation Law On December 29, 2022, the President signed into law (P.L. 117-328) the “Consolidated Appropriations Act, 2023.” The Act provides the following for NCATS: National Center for Advancing Translational Sciences For carrying out section 301 and title IV of the PHS Act with respect to translational sciences, $923,323,000: Provided, That up to $70,000,000 shall be available to implement section 480 of the PHS Act, relating to the Cures Acceleration Network: Provided further, That at least $629,560,000 is provided to the Clinical and Translational Sciences Awards program. Budget Request On March 28, 2022, the President’s Budget for FY 2023 was released. The FY 2023 budget request for NIH is $62.5 billion. The FY 2023 budget request for NCATS (PDF – 1.3MB) is $873.7 million. A 2-page NCATS fact sheet (PDF - 607KB) is also available. Click to view/download Congressional Justification FY 2023 Click to view/download fact sheet NCATS Budget Distribution This graphic is a representation of the relative size in terms of annual appropriation of NCATS’ four budget activities: Clinical and Translational Science Activities, Reengineering Translational Sciences, Cures Acceleration Network and Rare Diseases Research. Credit: National Center for Advancing Translational Sciences | ||||||||
| 279 | Studies of Tumor-Penetrating Microparticles for Pancreatic Cancer | Pancreatic cancer often is deadly because symptoms do not arise until the disease has become advanced. Less than 5 percent of pancreatic cancer patients live for five years after diagnosis. No effective treatments exist for late-stage pancreatic cancer. Cancer drugs (chemotherapy) mostly are given by mouth or intravenously (through an IV). However, it is hard to deliver high enough levels of the drug to tumors using these methods. A more direct way to deliver drugs to tumors in organs such as the pancreas is through the peritoneal cavity, the space surrounding the abdominal organs. Delivering cancer drugs by this method is called intraperitoneal (ip) chemotherapy. The investigators have developed an ip delivery method called tumor-penetrating microparticles (TPMs). TPMs are tiny particles that can be loaded with a drug, travel through the peritoneal cavity, enter a target tumor and deliver the therapy into the tumor. This project’s aim is to continue to develop this therapy to prepare it for human clinical trials. Although this version will be used to treat pancreatic cancer, the delivery method could be developed for treating a variety of other cancer types. Scientific Synopsis Pharmaceutical companies generally focus on drugs given by IV or oral administration. However, systemic therapy often does not deliver sufficient drug levels to solid tumors due to inadequate blood perfusion and high interstitial fluid pressure in tumors. On the other hand, intraperitoneal (ip) chemotherapy has demonstrated impressive survival advantage in multiple randomized trials. Due to the lack of approved ip products, these earlier studies used intravenous formulations. This approach has two limitations: (a) the restricted drug penetration to the tumor periphery diminishes the efficacy of ip treatment in patients with larger tumors, and (b) ip therapy is associated with infection due to indwelling catheter and with toxicity from high local drug levels, which produces abdominal pain. These problems have prevented widespread use of ip therapy in spite of the demonstrated efficacy. Our goal is to overcome these limitations and to address the unmet need of products suitable for ip treatments. The investigators have developed TPMs, a first-in-class delivery system tailored to the unique anatomical properties of the peritoneal cavity. TPMs are multicomponent, multifunctional, biocompatible, biodegradable, controlled-release polymeric micron-size particles. TPMs are designed to target, penetrate and deliver pharmacodynamically optimized drug levels to the superficial and deep layers of peritoneal tumors. TPMs represent a delivery platform that can be used to deliver small molecule therapeutics, biologics, gene vectors and imaging agents. The first generation TPM, TPM001, is loaded with paclitaxel. For patients with carcinomatosis, there are no therapeutic options and only palliative treatments (e.g., costly procedures such as repeated drainage of peritoneal fluid). The first indication for TPM001 is pancreatic cancer, which has a five-year survival rate of less than 5 percent. Lead Collaborators Optimum Therapeutics, LLC, San Diego Jessie L.-S. Au, Pharm.D., Ph.D. Ze Lu, Ph.D. Public Health Impact The goal of this project is to develop an effective treatment for locoregional control of metastatic pancreatic cancer and, more generally, peritoneal tumors, which affect 230,000 new patients annually in the United States. Outcomes BrIDGs program scientists are collaborating on the completion of formulation development, manufacture of Good Manufacturing Practice (GMP) drug product, and pharmacokinetic and IND-directed toxicology studies. | ||||||||
| 278 | Short Stabilized EPO-Peptide as Therapeutic Agents for Multiple Sclerosis and Acute Brain Trauma | Traumatic brain injury (TBI) is caused by a blow to the head that leads to loss of normal function of the brain. More than 1.7 million TBIs occur each year in the United States. TBI can cause permanent disability and even death. Multiple sclerosis (MS) is a disease in which the body’s own immune system mistakenly attacks the brain and spinal cord. The symptoms of this condition include trouble seeing, muscle weakness, numbness and tingling, trouble with balance, and problems with thinking and memory. MS affects more than 2.3 million people worldwide. No cure exists for either MS or TBI. In both conditions, damage to brain cells is caused by inflammation, which is the body’s response to injury or infection. The investigators have developed a drug that blocks nerve cell damage from inflammation. For this project, the researchers will continue to study the drug to prepare it for testing in human clinical trials. Scientific Synopsis The investigators have synthesized short cyclic erythropoietin peptides that are free of side effects, and the lead compound (JM4) is highly effective in blocking clinical progression and inflammatory neuropathology in preclinical animal models of TBI and MS. Both conditions are common human neurological disorders that affect every age group with long‐term consequences, and there is a pressing medical need to bring new, effective therapeutic agents for these diseases to patients. There is no effective therapy for acute TBI. Support from the BrIDGs program includes guidance and assistance on all aspects of the preclinical development process. With the support of NIH, the team is highly optimistic that it can carry this compound through phase I/II studies. Lead Collaborators Rutgers School of Dental Medicine, Newark, New Jersey Peter Dowling, M.D. Stuart Cook, M.D. Robert Heary, M.D. Public Health Impact The investigators have developed a new type of small molecule intervention that is effective in animal models of TBI and MS. Development of this compound, which has no side effects, for the clinic could lead to major advances in the treatment of these two conditions. Outcomes BrIDGs program scientists are collaborating on the completion of synthesis of Good Manufacturing Practice (GMP) and non-GMP material, formulation development and manufacture of clinical drug product, and IND-directed toxicology studies. | ||||||||
| 277 | Preclinical Development of EDN-OL1 for Alzheimer’s Disease | Alzheimer’s disease is a progressive brain disease. Early symptoms may include forgetfulness, apathy and depression, but late stages include an inability to communicate, care for oneself, walk or even swallow, and the disease is eventually fatal. An estimated 5.2 million Americans have Alzheimer’s, including 5 million over the age of 65. Alzheimer’s disease reduces the function of brain cells and the connections (called synapses) between them. Scientists think the accumulation of a protein called beta-amyloid and of an abnormal form of the protein tau contributes to this loss of function. Gradually, the transfer of information across the synapses begins to fail, the number of synapses declines and brain cells die. Alzheimer’s disease has no cure and no effective treatments. These scientists are developing a treatment for Alzheimer’s that acts by reducing the production of amyloid proteins in the brain. Scientific Synopsis More than 5 million Americans now have Alzheimer’s disease (AD), the sixth leading cause of death in the United States, and no disease-modifying drug is available. Edunn Biotechnology is a start-up company focused on development of antisense drugs for CNS indications. We request program assistance to carry out specific tasks for preclinical development of EDN-OL1 to support submission of an Investigational New Drug (IND) application to enable clinical trials for the Alzheimer’s indication, ultimately leading to FDA approval for treatment of AD patients. EDN-OL1, a patented antisense phosphorothioate oligonucleotide, crosses the blood-brain barrier after intravenous dosing and reduces production of amyloid precursor protein (APP) and, consequently, amyloid proteins in the brains of mouse models of AD. Edunn’s endpoint for EDN-OL1 efficacy in animal models has been to halt decline of cognitive function. In the three murine models tested, EDN-OL1 actually has restored cognitive function. The clinical benefit to AD patients may best be anticipated as a decrease in the rate of cognitive decline. We expect that patients would be maintained on one to four doses per month. EDN-OL1 efficacy does not require that any variety of late-onset AD arise from over-expression of APP because whatever the detailed ultimate pathology is, amyloid proteins are involved. Edunn plans separate development of an indication to treat CNS symptoms that result from the overexpression of APP that occurs in Down syndrome. Preclinical development includes the manufacture and animal safety testing of the active pharmaceutical ingredient. Edunn proposes to use program resources to complete selected preclinical development tasks required for submission of an IND. Lead Collaborator Edunn Biotechnology, St. Louis Thomas Darling, Ph.D. Public Health Impact Alzheimer’s disease takes a large economic and quality-of-life toll not only on patients but also on caregivers and society as a whole. The disease is the most important dementia of the aged, with characteristic senile plaques, loss of synapses and the presence of neurofibrillary tangles. However, no drugs on the market successfully halt or reverse the symptoms of Alzheimer’s disease. Outcomes The BrIDGs scientists completed an extensive chemistry, manufacturing and controls campaign for the active pharmaceutical ingredient. During conduct of the project, the business strategy of Edunn Biotechnology changed, and the collaboration was concluded. Project Details Synthesis of Good Manufacturing Practice (GMP) and non-GMP material Formulation development | ||||||||
| 276 | Divisions & Offices | NCATS has several divisions and offices with diverse staff who guide the center’s research activities. Office of the Director The Office of the Director develops and provides leadership for the center’s translational science programs, manages and directs executive level activities, and provides policy guidance and coordination for each of the center’s components. Division of Clinical Innovation The Division of Clinical Innovation (DCI) plans, conducts and supports research across the clinical phases of the translational science spectrum. This division: Plans, conducts and supports research to develop new methods and technologies to enhance clinical processes. Plans, conducts and supports research to evaluate existing and developing approaches, technologies, and processes in the clinical spectrum. Supports training programs relevant to clinical phases of translational science. Allocates DCI resources to clinical and translational infrastructure and investigators. Collaborates with other NIH Institutes and Centers and the scientists they support. Consults with stakeholders, including patients, industry and regulators. Division of Extramural Activities The Division of Extramural Activities advises NCATS leadership on issues related to policy and procedures for extramural activities. Additionally, it oversees and directs scientific review and grants management activities at NCATS. The division also manages the operations of the NCATS Advisory Council and Cures Acceleration Network Review Board. Division of Preclinical Innovation The Division of Preclinical Innovation (DPI) plans and conducts collaborative research projects across the preclinical phases of the translational science spectrum, using both internal and contract resources to advance them. Specifically, this division: Plans, conducts and collaborates on research to develop new methods and technologies to enhance preclinical processes. Plans, conducts and collaborates on research to evaluate existing and developing approaches, technologies, and processes in the preclinical spectrum. Supports training programs relevant to preclinical phases of translational science. Allocates DPI resources to preclinical extramural and intramural investigators. Collaborates with other NIH Institutes and Centers and the scientists they support. Consults with stakeholders, including patients, industry and regulators. Division of Rare Diseases Research Innovation The Division of Rare Diseases Research Innovation facilitates and coordinates NIH-wide activities involving research for a broad array of rare diseases. Specific duties include: Develops and maintains a centralized database on rare diseases. Coordinates and provides liaison with organizations worldwide concerned with rare diseases research and orphan products development. Advises the Office of the Director on matters related to NIH-sponsored research involving rare diseases. Responds to information and policy requests about rare diseases. The Division of Rare Diseases Research Innovation oversees NCATS programs, including: The Genetic and Rare Diseases (GARD) Information Center provides up-to-date health information about numerous rare and genetic diseases. The Rare Diseases Registry Program (RaDaR), formerly known as the Global Rare Diseases Registry Data Repository program, aims to define best practices for patient registries. RaDaR also strives to identify and adopt standards to support high-quality registries for rare diseases therapeutics development. The Rare Diseases Clinical Research Network (RDCRN) program is designed to advance medical research on rare diseases by providing support for clinical studies and facilitating collaboration, study enrollment and data sharing. The Platform Vector Gene Therapy (PaVe-GT) pilot project will test whether it is possible to increase the efficiency of gene therapy clinical trial startup by using the same gene delivery system and manufacturing methods for multiple gene therapies. Office of Administrative Management The Office of Administrative Management directs the administrative and financial operations management of the center. Specifically, it develops, administers and oversees the center’s internal control processes, policy and procedures for administration, program management and information technology. It also oversees personnel management and workforce planning. Office of Drug Development Partnership Programs The Office of Drug Development Partnership Programs (ODDPP) promotes innovations that improve the efficiency of drug development from target identification — including expanding the target landscape — through early-stage clinical trials. Programs administered by the ODDPP often involve partnerships with the private sector, other parts of NIH or the U.S. Government, and NCATS’ own intramural scientists. ODDPP also works with national and international stakeholders, providing leadership for the national response to public health emergencies. ODDPP programs and initiatives are listed as follows: The Biomedical Data Translator program is a collaboration that aims to integrate data and knowledge from vastly different biomedical domains to enable the discovery of associations not reported previously. LitCoin will generate machine-readable scientific literature and support more complete sharing of scientific observations, knowledge and data through bona fide literature-based credit. LitCoin launched in the fall of 2021 with a natural language processing challenge. The New Therapeutic Uses program implements approaches to improve the translational research pipeline by finding new uses for existing therapeutics, with the ultimate goal of accelerating the pace at which discoveries are turned into new preventions, treatments and cures for human diseases. ODDPP supports the Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, which is a nationwide effort to speed scientific solutions to stem the national opioid public health crisis. Researchers take a variety of approaches to tackle the opioid epidemic through understanding, managing and treating pain, as well as improving treatment for opioid misuse and addiction. The Illuminating the Druggable Genome (IDG) program is managed by the ODDPP in collaboration with the NIH Common Fund. IDG aims to expand the target landscape for drug development by providing foundational knowledge about understudied druggable proteins. Office of Policy, Communications and Education The Office of Policy, Communications and Education (OPCE) develops and communicates critical priorities for NCATS in a highly collaborative manner. The OPCE Policy Branch analyzes scientific and legislative issues relevant to translational science, works with NCATS stakeholders to develop and implement science policies, and addresses center-wide planning and strategic activities that are relevant to the spectrum of translational research. The OPCE Communications Branch develops and disseminates content that informs and engages a variety of audiences on NCATS programs, activities and impact. The OPCE Education Branch collaborates center-wide to develop and disseminate evidence-based tools and best practices to improve understanding of translational science, the skills necessary to become a translational scientist and the translational science spectrum. Office of Special Initiatives The Office of Special Initiatives (OSI) addresses translational problems with innovative solutions through the development and implementation of disruptive technologies using interdisciplinary approaches and novel public-private partnerships. The programs and initiatives within OSI are intended to be catalytic and transformative, resulting in a paradigm shift in the field. These efforts currently include the following programs and initiatives funded through NCATS’ Cures Acceleration Network: ASPIRE — A Specialized Platform for Innovative Research Exploration in automated chemistry initiative seeks to address biological targets with no known drugs by enlarging the chemical space universe via combining automation engineering and artificial intelligence/machine learning with synthetic chemistry and biological screening through novel collaborations between NCATS intramural laboratories and extramural scientists. ExTReMe — Exosome Therapy for Regenerative Medicine is a new program that seeks to catalyze the field of regenerative medicine through novel exosome-based therapeutics focusing on tissue repair and wound healing. Microfabricated tissues— 3-D Bioprinting — This program promotes collaborative partnerships between the intramural NCATS 3-D Tissue Bioprinting Laboratory and extramural research laboratories to significantly improve the drug development process by developing novel, physiologically relevant 3-D biofabricated disease tissue models for drug screening. Tissue Chips (Microphysiological Systems) for Drug Screening — This program develops an in vitro 3‑D culture system that emulates organ physiology and function using human cells and tissues through advances in stem cell biology, microfluidics and bioengineering for risk assessment to accurately evaluate the safety and efficacy of promising therapies and its use for precision medicine. National Science Foundation (NSF) collaborations — This trans-agency partnership between NIH and NSF involves two programs to support innovative research efforts: the National Robotics Initiative and Cyber-Physical Systems. SCENT — Screening for Conditions with Electronic Nose Technology is a new program designed to develop an electronic nose for disease diagnosis by detecting with high sensitivity and specificity the unique signatures of volatile organic compounds that are specific to every human disease or condition. START — Synthetic Technologies for Advancement of Research and Therapeutics is a new program that will use synthetic biology — along with newly available tools in genetic engineering, gene synthesis and metabolomics — to construct and incorporate new biosynthetic or artificial metabolic pathways to accelerate and enable the design and construction of engineered cell therapies for the production of compounds with strong therapeutic and disease relevance. The OSI also takes the lead on NIH-wide research activities that are supported through the NIH Common Fund. The current programs in which OSI plays an active role include the following: Extracellular RNA Communication for biomarker and therapy development SPARC — Stimulating Peripheral Activity to Relieve Conditions The OSI has had the opportunity to develop programs in response to current national health emergencies. Through the ASPIRE initiative and its ASPIRE Challenge, the OSI is involved in the Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, a trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. NIH launched the Rapid Acceleration of Diagnostics (RADx®) initiative to speed innovation in the development, commercialization and implementation of technologies for COVID-19 testing. In particular, for RADx-rad: Rapid Acceleration of Diagnostics radical technologies, the OSI is involved in developing two nontraditional technologies toward detecting SARS-CoV-2 virus: Screening for COVID-19 by Electronic-Nose Technology (SCENT) and Exosome-Based Non-traditional Technologies Towards Multi-Parametric and Integrated Approaches for SARS-CoV-2. Office of Strategic Alliances The Office of Strategic Alliances establishes and advances public-private partnerships, as well as develops innovative approaches, policies and methods to reduce, remove or bypass bottlenecks in translational science collaborations. Office of Translational Medicine The Office of Translational Medicine (OTM) uses expertise across clinical and other relevant disciplines to amplify NCATS’ ability to foster innovative translational science and improve health. OTM serves many offices and divisions within NCATS, including the Division of Clinical Innovation; the Division of Preclinical Innovation; the Division of Extramural Activities; the Office of Policy, Communications and Education; and the Office of Strategic Alliances. It is a repository of specialized knowledge, interprets and implements research-related policies, convenes stakeholders, and, in certain circumstances, arbitrates or makes decisions. Topics of interest to the Office include human subjects; diversity, equity, inclusion and accessibility; regulation and drug development; clinical research, including clinical trials and clinical epidemiology; and ethics, for which the Office operates a grant program. | ||||||||
| 275 | Peripheral CB1 Receptor Antagonist for Therapeutic Use in Metabolic Syndrome | Obesity has dramatically increased in the United States in recent decades; more than one-third of adults are obese. Obesity can lead to a variety of complications, including insulin resistance, buildup of fat in the liver and high cholesterol. Over time, these conditions can lead to diabetes, heart and liver disease, and cancer. No drugs exist that treat all of the complications of obesity. Recently, scientists tested a drug that blocks the activity of a type of chemical called endocannabinoids. These chemicals act as signaling molecules at the same receptors that recognize the active ingredient in marijuana, and they produce similar effects, including increased appetite and boosts in mood. The researchers found that the drug caused weight loss and reduced levels of insulin resistance, cholesterol and fat in the liver. However, the drug also caused depression and anxiety, making it not suitable for use as a therapy. The investigators have developed a drug that similarly blocks the effects of endocannabinoids but that cannot enter pass through the blood-brain barrier to produce unwanted psychological effects. The team will continue to prepare the drug for testing in human clinical trials of obesity and fatty liver disease. Scientific Synopsis During the last few decades, there has been an epidemic increase in the worldwide prevalence of obesity and its metabolic complications, including insulin resistance, diabetes, fatty liver and changes in blood lipid profile. These metabolic abnormalities, in turn, can lead to coronary heart disease, liver cirrhosis and certain forms of cancer. Currently, there is no available medication that simultaneously targets all of the metabolic consequences of obesity, justifying the search for novel approaches. Endocannabinoids are lipid‐like signaling molecules present in the brain as well as in peripheral tissues. They interact with the same cell surface receptors that also recognize the psychoactive ingredient in marijuana, and they produce similar effects, such as an increase in appetite and increased synthesis and decreased degradation of lipids. In recent clinical trials, researchers found that compounds that block the type‐1 cannabinoid (CB1) receptor were effective not only in reducing the weight of obese individuals, but also in reversing their associated insulin resistance, abnormal blood lipid profile and accumulation of fat in the liver. Unfortunately, these compounds also elicited depression and anxiety frequently, which makes them unsuitable for therapeutic use. Studies in animal models of obesity have indicated that the beneficial metabolic effects of CB1 receptor blocking drugs is mediated, at least in part, by blockade of CB1 receptors in peripheral tissues, including the liver, fat and skeletal muscle cells, whereas their neuropsychiatric side effects are due to blockage of CB1 receptors in the brain. The investigators have modified the chemical structure of currently available CB1 blocking drugs in a way that reduced their ability to penetrate the blood-brain barrier but did not affect their oral bioavailability, selectivity and high affinity for the CB1 receptor. When tested in mouse models of obesity, such compounds were equally as effective as their brain‐penetrant parent compounds in improving obesity‐related metabolic abnormalities, but they were devoid of the behavioral effects that predict neuropsychiatric effects in humans. The project team will carry out long‐term toxicology studies and oral formulation of a novel, peripherally restricted CB1 blocking compound for the treatment of the metabolic complications of obesity, primarily fatty liver disease with or without insulin resistance. Lead Collaborators National Institute on Alcohol Abuse and Alcoholism, NIH George Kunos, M.D., Ph.D. Jenrin Discovery, Inc., West Chester, Pennsylvania John McElroy, Ph.D. Robert Chorvat, Ph.D. Public Health Impact Obesity and its metabolic complications, including diabetes, changes in blood lipid profile and fatty liver disease have reached epidemic proportions worldwide. This class of compounds has the promise to be a novel and effective treatment of the metabolic abnormalities caused by obesity, and we propose to develop one such compound for testing in humans. Outcomes BrIDGs program scientists completed formulation development, manufacture of Good Manufacturing Practice (GMP) drug product, and pharmacokinetic and IND-directed toxicology studies As a result of BrIDGs support, the collaborators were able to file an IND application, which was cleared by the Food and Drug Administration in December 2017. The team is continuing to evaluate a high-dose formulation of the drug. | ||||||||
| 274 | Novel Pre-Hospital Therapy of Myocardial Infarction | Each year, approximately 160,000 people in the United States suffer from ST segment-elevated myocardial infarction (STEMI), a severe type of heart attack. Approximately half of all deaths from heart attacks occur before patients reach the hospital. Although emergency medical service providers commonly give heart attack victims aspirin, better pre-hospital therapies are needed. This project’s aim is to test a compound called RUC-4, which blocks a protein receptor on the surface of blood platelet (αIIbβ3) involved in blood clotting, and prepare it for human trials. The investigators hypothesize that injecting RUC-4 into the muscle of STEMI patients before they reach the hospital could help prevent death and heart damage from STEMI. Scientific Synopsis There has been relatively little improvement in pre-hospital therapy compared to the dramatic advances in therapy after arriving to the hospital. Our hypothesis is that the addition of a potent αIIbβ3 receptor antagonist administered intramuscularly (IM) via an autoinjector to standard oral aspirin in the pre-hospital therapy of patients with ST segment-elevated myocardial infarction (STEMI) will not only decrease early mortality, but will also decrease the development of congestive heart failure during the next 6-12 months. This hypothesis is based on evidence showing that therapy with other αIIbβ3 antagonists (along with aspirin) soon after symptom onset can abort the progression of thrombotic myocardial ischemia to irreversible cardiac damage and decrease mortality. Moreover, we expect a favorable safety profile since patients will neither be anticoagulated nor undergo arterial access in the pre-hospital setting, and the effects will wear off within 2-4 hours. Our specific aim is to obtain the pre-Investigational New Drug (IND) data needed to advance RUC-4, a novel αIIbβ3 antagonist, to human studies. RUC-4 was designed to be specific for αIIbβ3 and to have a unique mechanism of action that not only prevents ligand binding, but also prevents the conformational changes in the β3 subunit induced by current αIIbβ3 antagonists that have been implicated in causing thrombocytopenia and paradoxical receptor activation. RUC-4 was also designed to have high solubility so that the likely human dose can be administered by autoinjector. The current αIIbβ3 antagonists all must be administered intravenously, a major disadvantage for pre-hospital therapy. We currently have support from the NHLBI SMARTT program to produce RUC-4 to support the IND formulation and toxicology studies. The innovative aspects of this project include addressing an urgent unmet medical need, employing a novel compound with theoretical and practical advantages over current agents, proposing an innovative route of administration (IM) and method of delivery (via autoinjector), and proposing administration by Emergency Medical Service personnel in the pre-hospital setting. Lead Collaborator The Rockefeller University, New York, New York Barry Coller, M.D. Public Health Impact Annually, approximately 160,000 people in the Unites States experience STEMI according to the American Heart Association. The currently available antiplatelet agents have significant limitations and are challenging to provide in complicated emergency medical service conditions. New therapeutics like RUC-4 that are optimized for delivery in the pre-hospital setting could dramatically reduce the complications associated with STEMI. Outcomes BrIDGs program scientists completed formulation and process development, synthesis of Good Manufacturing Practice (GMP) material, and pharmacokinetic and IND-directed toxicology studies. As a result of BrIDGs support, an IND has been cleared by the FDA, allowing clinical trials to proceed. See ClinicalTrials.gov, NCT03844191. | The investigators hypothesize that injecting RUC-4 into the muscle of STEMI patients before they reach the hospital could help prevent death and heart damage. | Novel Pre-Hospital Therapy of Myocardial Infarction | The investigators hypothesize that injecting RUC-4 into the muscle of STEMI patients before they reach the hospital could help prevent death and heart damage. | Novel Pre-Hospital Therapy of Myocardial Infarction | ||||
| 273 | Manufacture of RLIP76-LyoPL for Acute Radiation Syndrome | Radiation exposure from a "dirty" bomb, a contaminated municipal water supply or a sabotaged nuclear reactor is a potential threat to national security. Exposure to radiation can lead to acute radiation syndrome (ARS), also called radiation sickness, a life-threatening illness that can damage or destroy multiple organs in the body. Currently, no treatment for the condition has been approved by the Food and Drug Administration (FDA). The investigators are working to develop RLIP76-LyoPL, a drug that can be given 24 hours or longer after radiation exposure. RLIP76-LyoPL prevents damage and death of cells injured by radiation. The drug could be given to civilians, military personnel and first responders as either a protectant against potential radiation exposure or as a treatment for ARS. Scientific Synopsis Radiation exposure can lead to ARS, a serious illness affecting multiple organs. Currently, radiation countermeasures (RCMs) are limited to supportive care only. The FDA has not approved any drugs to treat ARS, making RCMs a critical unmet need. Terapio Corp. is developing an RCM that could be used as either a pre-exposure prophylactic or a post-exposure mitigator for civilians, military personnel and first responders. Terapio has demonstrated efficacy of the drug RLIP76- LyoPL when administered 24 hours or longer after radiation exposure, a vital criterion for the Department of Health and Human Services (HHS) when considering an acquisition for the Strategic National Stockpile. Terapio’s therapeutic pipeline is based on RLIP76, a naturally occurring, membrane-associated transport protein encapsulated in a commercially available liposome that is lyophilized (RLIP76-LyoPL) using scalable methods. RLIP76 has a unique and known mechanism of action that allows it to prevent cell damage or death in the radiation cellular injury pathway. The long-term goal of the project is to provide HHS with a licensed RCM product for potential acquisition by the Strategic National Stockpile. NIH’s Radiation Nuclear Countermeasures program at the National Institute of Allergy and Infectious Diseases is co-funding the preclinical studies for this project. Lead Collaborator Terapio Corp., Austin, Texas Casey Cunningham, M.D. Public Health Impact Completion of scale-up and regulatory-compliant manufacturing of RLIP76-LyoPLmay enable Terapio to file a Biologics License Application with the FDA and provide HHS with a licensed RCM product for the Strategic National Stockpile that can be administered at least 24 hours after radiation exposure for the treatment of ARS. Outcomes BrIDGs program scientists completed process development, synthesis of non-GMP (Good Manufacturing Practice) drug substance, and manufacture of non-GMP drug product. Preclinical data did not warrant filing the Investigational New Drug application because efficacy data could not be reproduced with the non-GMP drug product. Work on this project is complete. | ||||||||
| 272 | Contribute to NCATS Research | Donations to NCATS are handled in a Gift Fund, which is separate from the appropriation received from Congress. Donations to the NCATS Gift Fund support the Center’s mission to transform how interventions to improve human health are developed, tested and delivered to patients. NCATS is an agency of the federal government and not a fundraising organization. However, Congress has authorized NCATS to accept donations and bequests to support the Center’s mission under the authority established in Sections 231, 405(b)(1)(H), and 497 of the Public Health Service (PHS) Act, as amended (42 U.S.C. §§238, 284(b)(1)(H), and 289f). How NCATS Uses Contributions Because NCATS' basic operating expenses and administrative costs are paid for using the congressional appropriation, donations are used for special projects in support of translational science. Projects supported through the Gift Fund vary from year to year depending on the needs of the Center. Following is a partial list of areas that can be supported through the Gift Fund: Special fellowships to train young scientists in translational research. Equipment for clinical laboratories. Workshops/conferences on subjects of special importance to translational research. Printing of materials about translational research. How to Contribute Individuals and organizations may contribute to the NCATS Gift Fund. Donations should include: A check or money order payable to the “National Center for Advancing Translational Sciences”. A letter indicating the type and purpose of the gift and contact information for the donor (see Gift Details below). Send donations to: Director, National Center for Advancing Translational Sciences One Democracy Plaza, 9th floor 6701 Democracy Boulevard, MSC 4874 Bethesda, Maryland 20892-4874 (20817 for express mail) Gifts to NCATS may be tax deductible; donators should consult a tax advisor for specific guidance. Gift Details Gifts may be “unconditional,” such as to support the NCATS mission, or “conditional,” such as to support a particular area of NCATS research. Memorial or honorary donations acknowledge a specific person. When making this type of donation, include the name and address of the honored individual in the donation letter. To include NCATS as a beneficiary in a will, the document should include the name and address of the Center as well as a statement that indicates the bequest is to be used to support NCATS’ mission. |
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