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| 271 | Long-Acting Parathyroid Hormone Analog for Treatment of Hypoparathyroidism | Hypoparathyroidism is a disorder in which the parathyroid glands in the neck do not make enough parathyroid hormone (PTH). PTH controls levels of calcium, phosphorus and vitamin D in the blood and in bones. Too little PTH leads to deficiencies in these vitamins and minerals, causing symptoms such as muscle twitching and seizures. Hypoparathyroidism can run in families, but a more common cause is injury to the parathyroid glands during surgery. No treatment currently exists to correct PTH deficiency; instead, patients are given large amounts of calcium and vitamin D, which can damage the kidneys. In previous clinical trials, patients were given PTH replacement therapy, but the version of PTH used was short-acting and had to be given by injection frequently. The investigators have developed a longer-lasting version of therapeutic PTH, the effects of which last 24 to 48 hours. They will continue to prepare the compound for testing in human clinical trials. Scientific Synopsis Hypoparathyroidism is a life-long disease of orphan-drug status that is characterized by an inadequate production of PTH, resulting in hypocalcemia and hyperphosphatemia. Instead of having their missing PTH replaced, affected individuals currently are given large amounts of oral calcium and active vitamin D analogs, treatments that increase considerably the risk of kidney damage (nephrocalcinosis and nephrolithiasis), even if blood calcium levels increase to only the lower end of the normal range. Clinical tests with subcutaneously administered PTH(1-34) and PTH(1-84) peptides of native sequence have demonstrated some efficacy; however, because of its short duration of action, at least two daily injections of PTH(1-34) are needed, and even then, serum calcium levels can fluctuate widely. Moreover, PTH(1-34) therapy often requires continued oral calcium and vitamin D supplementation, and urinary calcium excretion may not be reduced over the entire day with either PTH peptide. The key investigators have developed a novel class of long-acting PTH analogs that were selected for their unique biological properties at the PTH/PTHrP receptor (PTHR1). A single injection of these long-acting PTH peptides leads to a 24- to 48-hour sustained calcemic response in rodents and monkeys, which is accompanied by a sustained reduction in urinary calcium excretion and in blood phosphorus levels. Injection of either PTH(1-34) or PTH(1-84) failed to induce similarly prolonged effects. Among several of the long-acting PTH analogs identified, the investigators have selected LA-PTH, based on its superior potency in vitro and in vivo, for further development through BrIDGs. The team’s current data predict that LA-PTH can be more effective as a treatment for hypoparathyroidism than current modalities and that the new analog may be especially valuable for individuals with activating calcium-sensing receptor mutations, a particularly difficult-to-treat patient group who have an even higher risk of nephrocalcinosis and nephrolithiasis under conventional calcium and vitamin D therapy. Lead Collaborators Massachusetts General Hospital (General Hospital Corp.), Boston Michael Mannstadt, M.D. Thomas Gardella, Ph.D. Harald Jueppner, M.D. Robert Neer, M.D. John Potts, M.D. Public Health Impact Patients with hypoparathyroidism can suffer from multiple symptoms caused by low blood calcium levels. Symptoms can include minor problems like muscle twitching or severe, possibly life-threatening complications, such as seizures. The investigators have developed a long-acting PTH analog that is likely to provide major improvements over current medical therapy for this group of patients. Outcomes BrIDGs program scientists collaborated on the completion of formulation development, manufacture of Good Manufacturing Practice (GMP) and non-GMP material, including drug supply for clinical trials, and pharmacokinetic and IND-directed toxicology studies. | The investigators have developed a longer-lasting version of therapeutic PTH, the effects of which last 24 to 48 hours. | Long-Acting Parathyroid Hormone Analog for Treatment of Hypoparathyroi | The investigators have developed a longer-lasting version of therapeutic PTH, the effects of which last 24 to 48 hours. | Long-Acting Parathyroid Hormone Analog for Treatment of Hypoparathyroi | ||||
| 270 | IND-Enabling Preclinical Studies of 2DG for Treatment of Epilepsy | Epilepsy is one of the most common neurological disorders. More than 2 million people in the United States live with the disease, and an estimated 150,000 new cases are diagnosed each year. The disease stems from problems in the brain and is typified by recurring seizures caused when a group of brain cells begins to fire in an abnormal, synchronized way. Epilepsy is treated with a type of drug called an anticonvulsant, a variety of which are currently in use. Despite these drugs’ availability, as many as 50 percent of patients continue to have seizures and about 15 percent do not respond to any currently available anticonvulsants. These researchers are developing a new anticonvulsant drug that acts by stopping the bursts of brain cell activity that trigger seizures. It may also modify the disease so that more patients are amenable to treatment. Scientific Synopsis This proposal is for a preclinical program of pharmacokinetic, toxicological and CMC studies to complete an Investigational New Drug (IND) application that will advance the glucose analog 2DG into human clinical trials as a novel therapy for epilepsy. 2DG has been used for decades as a tracer in autoradiographic and PET imaging and unexpectedly was discovered to have novel anticonvulsant actions in acute and chronic experimental animal models of epilepsy. 2DG has a broad spectrum of action against a variety of cellular and network mechanisms underlying seizures and also impairs the progression of kindled seizures, implying that it may have “disease-modifying” actions against chronic consequences of seizures, which include susceptibility to intractability as well as cognitive and memory dysfunction. In addition to acute anticonvulsant actions, 2DG has novel “disease-modifying” effects when administered as long as 10 minutes after a seizure as a consequence of “activity-dependent” loading of 2DG into epileptogenic brain regions with high energy demands. These novel anticonvulsant, “disease-modifying” antiepileptic and “activity-dependent” actions distinguish 2DG from all currently marketed anticonvulsants. Preclinical toxicity studies of 2DG and human Phase I/II clinical trials of 2DG for treatment of cancer have demonstrated that doses effective against seizures are well-tolerated. Despite introduction of 11 new drugs for epilepsy since 1990, approximately 50 percent of patients have recurring seizures and approximately 15 percent are medically intractable. The pharmacokinetic, toxicological and CMC studies proposed in this RAID application build on already completed preclinical studies conducted at the University of Wisconsin and NeuroGenomeX, Inc., and will enable submission of an IND application to advance 2DG into human clinical trials as a novel promising treatment for epilepsy, with potential to increase the number of patients who achieve control and favorably modify adverse consequences in patients in whom complete control is not achieved. Lead Collaborator University of Wisconsin–Madison Thomas Sutula, M.D., Ph.D. Public Health Impact There is a need to develop anticonvulsants with novel mechanisms of action that increase the number of patients achieving complete seizure control and for antiepileptic disease-modifying therapies that treat the progressive adverse effects of repeated seizures on neural circuits. 2DG, with its anti-glycolytic action and novel mechanism of metabolic regulation of gene transcription contributing to seizure-induced plasticity, represents an entirely new therapeutic approach for treatment of seizures and for reducing the consequences of epilepsy. Outcomes Approved studies are ongoing. Project Details Synthesis of Good Manufacturing Practice (GMP) and non-GMP material Formulation development, manufacture of clinical dosage form Pharmacokinetic studies IND-directed toxicology Publication 2-Deoxy-d-Glucose (2-DG)-Induced Cardiac Toxicity in Rat: NT-proBNP and BNP as Potential Early Cardiac Safety Biomarkers • International Journal of Toxicology • Feb. 2, 2016 | ||||||||
| 269 | About the Center | At NCATS, we tackle ongoing challenges in research so that new treatments can reach people faster. We focus on what is common across diseases and develop solutions that reduce, remove or bypass bottlenecks in the translational process. Our vision is more treatments for all people more quickly. Learn more about the Center below or visit our fact sheets page for more details about Center activities. At a Glance About the Director Get to know Joni L. Rutter, Ph.D., and read her Director's Messages, where she discusses NCATS' priorities. Advisory Groups Find information about and meeting schedules for the NCATS Advisory Council and the Cures Acceleration Network Review Board. Budget Access information about NCATS' budget, including the annual NCATS Congressional Justifications, which provide the Senate and House Appropriations Committees with estimates and justifications for NCATS research and research support activities. Divisions & Offices Learn about the roles of NCATS' divisions and offices in supporting a comprehensive translational science research agenda. Job Opportunities Find current job openings across our dynamic team for executive, administrative and scientific positions, including training opportunities and fellowships. Work with NCATS Explore opportunities to collaborate with NCATS scientists, funding programs and resources we offer to help researchers translate basic scientific knowledge into interventions that improve human health. Learn More About Us NCATS Staff Profiles Learn more about our staff members and their work in support of the Center's mission. NCATS Strategic Plan View our strategic plan, which outlines our goals and specific objectives. NCATS History Read about NCATS' founding vision, legislation establishing the Center, biennial reports and more. | NCATS is transforming the translational process to get more treatments to all people more quickly. | /sites/default/files/NCATS_default_metaimage_tagline_FINAL_0.png | About the Center | NCATS is transforming the translational process to get more treatments to all people more quickly. | /sites/default/files/NCATS_default_metaimage_tagline_FINAL_1.png | About the Center | ||
| 268 | HBN-1 Regulated Hypothermia Formulation and Evaluation of Toxicity | More than 325,000 cardiac arrests occur each year in the United States. A cardiac arrest, when the heart suddenly stops beating, causes loss of consciousness and death if untreated after several minutes. Patients who are revived from cardiac arrest can suffer from brain injury due to lack of blood flow to the brain during the event. Therapeutic hypothermia, in which a patient’s body temperature is lowered, can help prevent brain injury after cardiac arrest. Currently, health care providers lower body temperature with a combination of ice bags, cooling pads and drugs. However, less than 12 percent of hospitals use therapeutic hypothermia because it is complex, it can take too much time and the drugs can be dangerous. This project’s investigators will develop a drug called HBN-1 that causes hypothermia by affecting the brain region that controls body temperature. This new approach would allow paramedics to inject the drug intravenously (through an IV) to more quickly and safely induce therapeutic hypothermia. Scientific Synopsis Patients resuscitated from cardiac arrest often suffer devastating brain damage. Therapeutic hypothermia dramatically improves survival with good neurological outcomes in more than half of patients who remain comatose after cardiac arrest. Given this evidence, the American Heart Association and International Liaison Committee on Resuscitation (ILCOR) incorporated therapeutic hypothermia into their 2010 treatment guidelines. To lower body temperature, medical personnel currently use mechanical methods, including ice bags, cooling pads and endovascular devices to forcefully lower body temperature. Used alone, these methods cannot completely induce hypothermia because of the body’s ability to tightly thermoregulate with shivering, vasoconstriction and increased metabolism. As a result, potentially dangerous agents such as narcotics and paralyzing drugs must be given to enhance the cooling process. Less than 12 percent of hospitals use therapeutic hypothermia because the current cooling methods are considered complex and potentially dangerous. The investigators developed HBN-1 as a simple and effective alternative to forced cooling to induce therapeutic hypothermia. HBN-1 induces regulated therapeutic hypothermia and neuroprotection. Regulated hypothermia is a drug-induced lowering of the body’s temperature set point in the hypothalamus. When the set point is lowered, the body lowers metabolism, blocks shivering and increases heat loss through peripheral vasodilatation and sweating. HBN-1 is a patented pharmaceutical preparation that induces rapid and prolonged regulated hypothermia at room temperature without paralysis, sedation, ancillary equipment or need for mechanical ventilation. The formulation is administered intravenously so paramedics can give it in the field to minimize delays in inducing therapeutic hypothermia. HBN-1 provides a new approach for inducing and maintaining therapeutic hypothermia and overcoming the current barriers to its use in hospitals. Lead Collaborator University of North Carolina at Chapel Hill Laurence Katz, M.D. Public Health Impact Patients with severe brain damage cannot care for themselves or enjoy the normal activities of daily living. Increased use of therapeutic hypothermia could prevent or lessen brain damage, shorten time to discharge from the hospital and reduce health care costs. 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, an IND has been cleared by the FDA, allowing the lead collaborators to initiate clinical trials. See ClinicalTrials.gov, NCT04094857. | This project’s investigators will develop a drug called HBN-1 that causes hypothermia by affecting the brain region that controls body temperature. | HBN-1 Regulated Hypothermia Formulation and Evaluation of Toxicity | This project’s investigators will develop a drug called HBN-1 that causes hypothermia by affecting the brain region that controls body temperature. | HBN-1 Regulated Hypothermia Formulation and Evaluation of Toxicity | ||||
| 267 | Evaluation of ACT1 to Treat Diabetic Keratopathy | An estimated 29.1 million people in the United States have diabetes, and its prevalence is rising. Diabetes is a leading cause of blindness and vision problems. Diabetic keratopathy, which occurs in about half to two-thirds of people with diabetes, is a condition that produces chronic injury and damage to the cornea, the clear outer part of the eye. This project will involve further development and safety studies of ACT1, a potential therapeutic compound for diabetic keratopathy. ACT1 enhances wound healing by blocking the action of a protein that promotes injury signals. In addition to diabetic keratopathy, ACT1 could be used to treat cornea injuries due to military activities or eye surgery. This project will prepare ACT1 for testing in humans. Scientific Synopsis Diabetes is a leading cause of blindness and visual impairments. Diabetic keratopathy, characterized by corneal thinning, disorganization, and persistent epithelial defects, is recognized as a significant cause of morbidity associated with the disease, presenting in an estimated 47-64% of diabetics. Unlike in normoglycemic individuals, diabetic corneal defects are associated with abnormal corneal re-epithelialization and individuals with diabetes present with persistent corneal wounds that are unresponsive to conventional treatment regimens. FirstString Research is a clinical stage biotech company with clinical success in developing therapeutic peptides for applications in tissue engineering and regenerative medicine. FirstString’s lead peptide, ACT1, is based on the C-terminal sequence of connexin43 (Cx43) and is designed to enter the cell and competitively inhibit the binding of endogenous Cx43. Cx43 plays critical roles in multiple aspects of wound healing, including spread of injury signals, extravasation of immune cells, granulation tissue formation, and fibrosis. A topical gel formulation of ACT1 (Granexin) is in Phase III clinical development for chronic wound healing and scar reduction. Studies in preclinical models of efficacy show significant enhancement in corneal re-epithelialization and wound closure following ethanol-induced corneal burn injuries in diabetic rats, as compared with controls. Given the success of ACT1 in dermal indication programs and the positive preclinical efficacy outcomes in relation to corneal healing, the objectives of this BrIDGs application are aimed at safety evaluation and optimization of an ACT1 formulation with the goal to complete a preclinical safety package for an Investigational New Drug (IND) application and pave the way for human clinical evaluation. In addition to addressing the medical needs of an expanding diabetic population, this formulation may be applicable in corneal injuries resulting from military engagement or corneal epithelial damage obtained during cataract or corneal refractive surgery. Lead Collaborator FirstString Research, Inc., Mount Pleasant, South Carolina Gautam Ghatnekar, Ph.D. Public Health Impact Reports from the American Diabetes Association indicate that an estimated 29.1million people in the US have diabetes. The chronic nature of diabetes, severity of its complications, and the disease management resources puts an enormous economic and societal burden on the individual, family, and healthcare system. Outcomes BrIDGs program scientists are collaborating on completion of formulation development, and pharmacokinetic and IND-directed toxicology studies. | ||||||||
| 265 | University of Florida Clinical and Translational Science Institute | Gainesville, Florida Principal InvestigatorDavid Robert Nelson, M.D., University of Florida Website To speed the translation of basic science discoveries to early investigations in humans and the translation of clinical research into better medical practice and health care delivery, the University of Florida (UF) has invested in new research and training resources and restructured its traditional reporting, research and training operations to create the Clinical and Translational Science Institute (CTSI). The institute will provide the intellectual home for clinical and translational research and training, integrating and synergizing the scientific and educational activities of 12 colleges, two academic and clinical campuses, two regional health care systems and Florida's 67 counties. CTSI aims to: Create an environment through which individuals from diverse disciplines can interact; resources, services and technologies can be identified and accessed; and local and regional barriers to collaborative research can be overcome; Train a workforce of clinical and basic science investigators, clinical trialists, laboratory technicians, study coordinators and other personnel required to establish and support multi- and interdisciplinary clinical and translational research teams; Enhance the quality and availability of cutting-edge technologies and novel research programs to accelerate discovery, development and application of diagnostic and therapeutic modalities; and Create opportunities for clinical scientists and Floridians to collaborate in advancing education and research into the causes, prevention, diagnosis, treatment and cure of human disease. CTSI will enable UF to transform how it conducts multi- and interdisciplinary clinical and translational research and training and how it engages citizens across Florida in community-based participatory research, education, health care and health care delivery. | ||||||||
| 264 | Yale Center for Clinical Investigation | New Haven, Connecticut Principal Investigator Robert S. Sherwin, M.D., Yale University Website The Yale Center for Clinical Investigation (YCCI) was created to provide a home for training the next generation of clinical investigators. Key programmatic goals are: Attract highly talented students and junior faculty across medicine, nursing, public health, biological sciences and biomedical engineering; train them in the use of state-of-the-art research tools; give them the skills to work within complex research teams; and support their professional development. Foster the translation of disease-related discoveries from the laboratory into the community by stimulating the creation of interdisciplinary teams; making available state-of-the-art core facilities and expanded biostatistical and bioinformatics resources; establishing organizational and regulatory infrastructure for clinical studies; and forging a dynamic new partnership that will integrate community leaders, physicians and health centers. Participating institutions include the schools of medicine, nursing and public health; the Department of Biomedical Engineering; and graduate programs in biological and biomedical sciences. The investigative medicine program (IMP) is central to YCCI's education and training efforts. It is a unique doctoral program that offers Ph.D. degrees in health sciences research to highly qualified M.D. fellows embarking on careers in translational or clinical research. IMP will be expanded with CTSA Program support to include nursing, public health biological sciences, and M.D.-Ph.D. students. YCCI has also created a Society of YCCI Faculty Mentors who will participate actively in the training and nurturing of the students and junior faculty members identified as YCCI Clinical Scholars. Pilot and feasibility grants will be awarded for junior faculty, interdisciplinary translational teams, new technologies and community-based projects. YCCI will cluster research cores around common themes, including imaging, specimen analysis, physiology, cognition and behavior, drug development, and cell therapy. A new office of research services will provide facilities for one-stop shopping for regulatory, biostatistical, bioinformatics, recruitment and other support services. YCCI will have an office to coordinate the university's efforts to address health issues facing our community. The university's decision to immediately provide substantial support to establish the YCCI reflects its strong commitment to an innovative redesign of our clinical and translational research activities. | ||||||||
| 263 | Weill Cornell Clinical and Translational Science Center | New York, New York Principal InvestigatorJulianne L. Imperato-McGinley, M.D., Weill Cornell Medical College Website The Clinical and Translational Science Center (CTSC) — comprising public/private institutions on the Upper East Side of Manhattan — is a unique and diverse biomedical complex, providing investigators with state-of-the-art resources for conducting clinical and translational research. Weill Cornell Medical College of Cornell University, the lead institution, serves as a conduit through which technological resources and educational programs are efficiently shared and managed. Neighboring institutions contribute significantly to the CTSC. Hospital for Special Surgery, a leader in investigating musculoskeletal and autoimmune diseases, is one of two medical institutions designated by NIH as a Core Center for Skeletal Integrity. Memorial Sloan-Kettering Cancer Center is a cancer center where state-of-the-art basic science research flourishes side-by-side with clinical investigation and treatment at Memorial Hospital. Cornell University Cooperative Extension, NYC, engaged in research addressing the needs of a changing New York for over 50 years, will be the linchpin for community outreach. Hunter College Gene Center's Research Center for Minority Institutions recruits and nurtures minority talent and has established an effective electronic network with minority scientists nationwide. Hunter College School of Nursing, training nurses from a diverse urban population, will participate in community outreach and education in underserved areas. | ||||||||
| 262 | Washington University in St. Louis Institute of Clinical and Translational Sciences | St. Louis, Missouri Principal Investigator Bradley Evanoff, M.D., M.P.H., Washington University in St. Louis Website The Institute of Clinical and Translational Sciences (ICTS) was created in 2007 as the academic home and primary advocate for clinical and translational science in Missouri and southern Illinois by building on three translational research pillars: infrastructure and resources, outstanding KL2 and TL1 educational programs, and increasing cross-disciplinary scientific collaborations. Over the past nine years, the ICTS has transformed culture and practice around translational research at Washington University (WU) and its partnering health care system BJC HealthCare, and fostered new partnerships with St. Louis University (SLU), the St. Louis College of Pharmacy (STLCOP), and the University of Missouri-Columbia (MU). In addition, the ICTS has initiated an unprecedented level of partnership with other academic, health care, community and scientific institutions in the region including key organizations promoting community health and biomedical and pharmaceutical companies in the St. Louis area. The ICTS leverages WU strengths in dissemination and implementation, imaging, and genomics coupled with major partner strengths in vaccine development and the Center for World Health and Medicine (SLU), clinical pharmacology (STLCOP), and veterinary medicine, journalism, and nursing research (MU). New ICTS functions and components enable members to continue and extend past successes in clinical and translational research. Several newer areas of focus have been introduced in order to promote cross-cutting themes, including: 1) a translational genomics function that will speed incorporation of clinical genomics into health care; 2) an implementation science and entrepreneurship function that will leverage the untapped synergy between these two highly complementary fields to increase the ability of translational researchers to develop effective, scalable and sustainable interventions and products that improve human health; and 3) an emphasis on clinical trials, especially multicenter trials, through the establishment of innovative services to streamline investigators' ability to recruit research participants from diverse populations, use a central Institutional Review Board and master trial agreements, receive regulatory guidance services, and work with partner organizations in the CTSA network. The impact of ICTS programs and services, as evaluated by analysis of publications, collaboration, external funding, and practice/policy change, is described on the ICTS Impact Web page. | ||||||||
| 261 | Virginia Commonwealth University Center for Clinical and Translational Research | Richmond, Virginia Principal Investigator F. Gerard Moeller, M.D., Virginia Commonwealth University Website Effective delivery of research that moves from the bench to the bedside to the community requires a transformation of research practice at every level. To accomplish this, Virginia Commonwealth University (VCU) has established the VCU Center for Clinical and Translational Research (CCTR), a comprehensive matrix center that supports VCU's efforts to strengthen ties with affiliates and community partners to better share resources and respond to community health needs. CCTR facilitates new partnerships and initiatives, extending the university's research base of federal, private and industry sponsors. Combining VCU's existing resources with those of the CTSA Program award, CCTR supports novel research methods in three areas of strength: substance abuse, women's health and rehabilitation science; pilot funds support innovation and community engagement research in these areas. Through CCTR, researchers benefit from centralized management, web-based data sharing, training and access to a rich array of resources, including biostatistics, ethics, research study and regulatory support. In addition, students can pursue a transdisciplinary education through the center's M.S. and Ph.D. degree programs in clinical and translational science. |
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