| ID | Title | Body | Facebook Description | Facebook image | Facebook Title | Facebook Video | Twitter Description | Twitter Image | Twitter Title | Meta tags |
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| 302 | Funding Policy & Scientific Review | NCATS gives priority to resources and projects that catalyze innovation in translational science and enable the biomedical research community to realize the potential of science to deliver tangible improvements in human health. Learn more about NCATS funding and award decisions: Funding Policy Scientific Review Cures Acceleration Network | ||||||||
| 301 | Inhibitors of Glutaminase 2 as Therapeutic Agents for Neuro-Oncological Diseases and Celiac Sprue | Neuro-oncological diseases, such as glioblastoma multiforme (brain cancer), sometimes called meningioma, can start from brain cells, the membranes around the brain (meninges), nerves or glands. Tumors can directly destroy brain cells. They also can damage cells by producing inflammation, placing pressure on other parts of the brain and increasing pressure within the skull. It is estimated that more than 14,000 people will die from brain and other nervous system cancers in 2014. This new experimental drug blocks the action of an enzyme called transglutaminase 2, which is believed to play an important role in neuro-oncological diseases. Scientific Synopsis Transglutaminase 2 (TG2), an extracellular enzyme found in many organs, catalyzes the formation of protein-protein crosslinks in the extracellular matrix. It is believed to play an important role in the pathogenesis of diverse human disorders, including certain neuro-oncological diseases and celiac sprue. The medicinal attractiveness of this protein target is underscored by the observation that TG2 knockout mice lack developmental, physiological or reproductive defects. A lead compound, KCC009, has been evaluated as an inhibitor of human TG2 and shows considerable promise as a chemo-sensitizing and radio-sensitizing agent for the treatment of glioblastomas, meningiomas and melanomas. Preliminary data also suggest that orally administered KCC009 may have suitable pharmacokinetic and pharmacodynamic features for treating celiac sprue. This proposal seeks support from the program to evaluate the therapeutic utility of KCC009. Specifically, we propose to test whether TG2 inhibition selectively sensitizes glioblastomas, meningiomas and melanomas to chemotherapy with an alkylating agent and/or radiation therapy. Lead Collaborators Stanford University, California Chaitan Khosla, Ph.D. Washington University School of Medicine, St. Louis Keith M. Rich, M.D. Public Health Impact Given the large and growing body of data that implicates TG2 in the pathogenesis of several unmet medical needs, including neuro-oncological diseases, such as glioblastoma multiforme, meningioma and metastatic melanoma, and inflammatory diseases of the small intestine, such as celiac sprue, the availability of an experimental therapeutic agent has enormous potential for impact at an exceptionally broad level. Moreover, based on available data from TG2 knockout mice as well as multiple dosing studies with KCC009 in rodents, this mode of therapy appears to have attractive safety considerations. Outcomes Work on this project is complete. Project Details Synthesis of Good Manufacturing Practice (GMP) material Development of an IV and oral formulation Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies Investigational New Drug (IND)-directed toxicology | ||||||||
| 300 | IND-Enabling Toxicology and Safety Pharmacology Studies for a First-in-Class CPG-Activating Drug Treatment (SPINALON) Against Chronic Spinal Cord Injury | Spinal cord injury can cause complete loss of motor control and loss of feeling in both the legs and the arms. Such an injury is permanent and has no cure. About 5,000 spinal cord injuries occur each year in the United States. The extent of the impairment depends on where on the spinal cord the injury occurs and its severity. The health effects can far exceed the lack of mobility. In the worst cases, a person may need complete care and have no voluntary bodily function from the neck down. Inactivity can lead to respiratory infections and heart disease, among other complications. These researchers are developing a medical treatment for spinal cord injury that allows a patient to make stepping motions for 45 to 60 minutes at a time. Such activity a few times each week could help reverse some of the physical deterioration that accompanies inactivity. The treatment works by temporarily activating the spinal locomotor network but does not heal the spinal cord lesion itself. Scientific Synopsis Spinal cord injury (SCI) is an irreversible condition for which no curative treatment is currently available. The consequences are complex and not limited to paralysis per se. Indeed, with time, the state of paralysis and chronic immobility lead to severe health problems such as cardiovascular problems, osteoporosis, muscle atrophy, immune system deficiency and life-threatening infections. Consequently, in 2002, we launched a research program supported by several not-for-profit foundations and agencies (e.g., Christopher & Dana Reeve Foundation) aimed at further understanding spinal locomotor network-activating mechanisms and, hence, at developing a palliative treatment against paralysis-/immobility-related health problems. In 2004–2005, after three years of drug screening, we discovered a drug combination (Spinalon) essentially composed of small molecules belonging to the families of monoamine receptor agonists, noradrenaline/dopamine precursors and decarboxylase inhibitors. Upon systemic delivery (s.c., i.p., or p.o.), Spinalon was found to potently activate the spinal locomotor network (often referred to as central pattern generator or CPG) localized mainly in the lumbar segments and, thus, sustained involuntary stepping movements during 45–60 min in the lower limbs of chronic and complete paraplegic mice (completely low-thoracic-transected). These exciting proof-of-concept data also included comparable observations in turtles, suggesting a phylogenetically well-conserved mechanism of action throughout vertebrates. Optimization, clinical utility and first-in-man (a case report) experiments were also conducted. According to independent experts in the field of drug development, Spinalon is now ready to undertake final preclinical testing. Consequently, the present proposal seeks full support to perform preclinical tests in animals, including (1) safety pharmacology in dogs and rats, (2) pharmacokinetics in rats, (3) single-dose and 14-toxicity in rats, and (4) development of analytical/bioanalytical assays. We also seek support for Investigational New Drug (IND) planning and preparation as well as to explore stability of one or two final formulations (i.e., oral and/or sublingual). Upon completion of the proposed work by NIH, NeuroSpina, a biotech company based in Quebec City, has been designated to proceed and to undertake, in collaboration with partners and CROs, the first clinical trials with Spinalon (PI/IIa). In summary, this innovative therapeutic approach may allow SCI patients (i.e., specifically, motor-complete ASIA A or B patients who may benefit the most) to become physically active (treadmill training) a few times weekly. Evidence from animals and humans suggests that such an approach may lead to a safe first-in-class palliative treatment designed to prevent and even reverse health degradation and life-threatening problems associated with chronic immobility due to SCI. Lead Collaborator Université Laval, Quebec City, Canada Pierre A. Guertin, Ph.D. Public Health Impact A drug combination called Spinalon was found to temporarily induce, with no other forms of assistance, locomotor movements in motor-complete spinal cord–injured animals. This innovative therapeutic may thus become a first-in-class treatment as well as a simple and affordable approach against the many severe health problems typically associated with paralysis and chronic immobility. Outcomes Work on this project is complete. The investigator successfully filed a Clinical Trial Application with Health Canada using BrIDGs data and initiated clinical testing. Project Details Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies | ||||||||
| 299 | Translational Science Spectrum | The translational science spectrum represents each stage of research along the path from the biological basis of health and disease to interventions that improve the health of individuals and the public. The spectrum is not linear or unidirectional; each stage builds upon and informs the others. At all stages of the spectrum, NCATS develops new approaches, demonstrates their usefulness and disseminates the findings. Patient involvement is a critical feature of all stages in translation. window.onload = function() { preloadImage('/files/TranslationalScienceSpectrumGraphicClinicalImplementation_FV_600x634.jpg'); preloadImage('/files/TranslationalScienceSpectrumGraphicClinicalResearch_FV_600x634.jpg'); preloadImage('/files/TranslationalScienceSpectrumGraphicBasicResearch_FV_600x634.jpg'); preloadImage('/files/TranslationalScienceSpectrumGraphicPreclinicalResearch_FV_600x634.jpg'); preloadImage('/files/TranslationalScienceSpectrumGraphicPublicHealth_FV_600x634.jpg'); }; function preloadImage(url) { (new Image()).src = url; } function dottedLine(section) { var imgSrc = '/files/TranslationalScienceSpectrumGraphic' + section + '_FV_600x634.jpg'; document.getElementById('map1').src = imgSrc; } function baseBackground(section) { var imgSrc = '/files/TranslationalScienceSpectrumGraphicStatic_FV_600x634.jpg'; document.getElementById('map1').src = imgSrc; } Basic Research Basic research involves scientific exploration that can reveal fundamental mechanisms of biology, disease or behavior. Every stage of the translational research spectrum builds upon and informs basic research. NCATS scientists typically do not conduct basic research; however, insights gained from the Center’s studies along the translational spectrum can inform basic research. Preclinical Research Preclinical research connects the basic science of disease with human medicine. During this stage, scientists develop model interventions to further understand the basis of a disease or disorder and find ways to treat it. Testing is carried out using cell or animal models of disease; samples of human or animal tissues; or computer-assisted simulations of drug, device or diagnostic interactions within living systems. Clinical Research Clinical research includes studies to better understand a disease in humans and relate this knowledge to findings in cell or animal models; testing and refinement of new technologies in people; testing of interventions for safety and effectiveness in those with or without disease; behavioral and observational studies; and outcomes and health services research. The goal of many clinical trials is to obtain data to support regulatory approval for an intervention. Clinical Implementation The clinical implementation stage of translation involves the adoption of interventions that have been demonstrated to be useful in a research environment into routine clinical care for the general population. This stage also includes implementation research to evaluate the results of clinical trials and to identify new clinical questions and gaps in care. Public Health In this stage of translation, researchers study health outcomes at the population level to determine the effects of diseases and efforts to prevent, diagnose and treat them. Findings help guide scientists working to assess the effects of current interventions and to develop new ones. | The translational science spectrum represents each stage along the path from basic research to developing and disseminating interventions that improve health. | /sites/default/files/TranslationalScienceSpectrumGraphicInteractive_600x600_2_1.png | Translational Science Spectrum | The translational science spectrum represents each stage along the path from basic research to developing and disseminating interventions that improve health. | /sites/default/files/TranslationalScienceSpectrumGraphicInteractive_600x600_3_1.png | Translational Science Spectrum | ||
| 298 | IND-Enabling Studies on AAV2-GDNF for Parkinson’s Disease | Parkinson’s disease is a progressive disorder of the nervous system in which brain cells gradually deteriorate and die, causing a decrease in dopamine in the brain. This leads to abnormal brain activity and symptoms of disease. Scientists do not fully understand the causes of Parkinson’s, but it may have both genetic and environmental components. Progression of Parkinson’s varies from person to person, but in its later stages, a person may require nearly total care. As many as 1 million Americans live with the disease, and about 60,000 new cases are diagnosed each year. Men are at higher risk for Parkinson’s than women, and risk increases with age. Currently there is no cure, although medications are available to help control many of the symptoms. These researchers are developing a gene therapy for Parkinson’s that will act by helping to reduce the loss of key, dopamine-producing brain cells. Scientific Synopsis The overall aim of this program is to acquire all of the outstanding preclinical data required for submission of an Investigational New Drug (IND) application for the development of AAV2-GDNF as a treatment for Parkinson’s disease (PD). Over the last decade, it has become clear that glia-derived growth factor (GDNF) exhibits remarkably potent trophic effects upon dopaminergic neurons of the substantia nigra. Loss of these key neurons underlies many of the movement and psychological deficits in the disease. A major technical challenge to GDNF therapy has been the development of a means to deliver this small protein into the brain in a focused and predictable manner. On this basis, we have been developing a gene therapy approach to solving this problem. Pre-IND discussions with the FDA have defined a series of preclinical studies that must be completed before we are in a position to file an IND. We are near completion of two major safety and efficacy studies in non-human primates. These studies incorporate analyses and end-points suggested by the FDA and include determinations of organ pathology, including neuropathology, specifically addressed in this proposal. In addition, qualification of GMP vector to be manufactured at Children’s Hospital of Philadelphia (CHOP) requires that a GLP toxicity study in rats be commissioned, and this also includes extensive organ pathology and biodistribution. Specifically, therefore, we propose that the following activities be supported under the program in support of our IND-enabling studies: GMP manufacture of AAV2-GDNF at CHOP GLP toxicity study in normal rats Biodistribution study Neuropathological assessments of rodent and NHP brain These studies, along with supporting data accrued at UCSF, would enable compilation of an IND. If accepted by the FDA, we would be in a position to undertake a well-designed, NIH-supported clinical study of the safety and efficacy of AAV2-GDNF gene therapy for Parkinson’s disease. Lead Collaborator University of California, San Francisco Krzysztof Bankiewicz, M.D., Ph.D. Public Health Impact Translation of AAV2-GDNF gene therapy into clinical study is likely to improve prospects for significant reversal of the symptoms of Parkinson’s disease. Outcomes Work on this project is complete. The investigators successfully filed an IND application using BrIDGs data and initiated clinical testing. Project Details Investigational New Drug (IND)-directed toxicology | ||||||||
| 297 | Development of P-321 for Chronic Dry Eye | Dry eye is one of the most frequently diagnosed diseases of the eye, affecting more than 5 million people in the United States. The condition can cause redness, irritation and vision problems. Only a few treatments currently exist for the condition, and they only provide temporary or partial relief. The epithelial sodium channel is a protein found on the surface of many tissues in the body, including the eye. This protein controls hydration by controlling the levels of salt and water absorbed by the surface of the eye. The investigators have developed a drug that inhibits the action of the epithelial sodium channel, preventing salt and water from being absorbed and keeping the eye surface hydrated. This project’s aim is to further develop this drug to prepare it for testing in human clinical trials. Scientific Synopsis Dry eye is a multi-factorial disease, resulting from a common etiology of insufficient tear film causing ocular surface damage and symptoms of ocular discomfort. The few current therapies available, which include immunosuppressive agents and over-the-counter tear replacements, are not sufficiently efficacious for many users or only provide transient relief from dry eye symptoms. Therefore, the development of novel agents to treat dry eye would be of tremendous benefit. The volume of tear film on the ocular surface represents a balance between tear fluid output versus fluid loss via drainage, evaporation or epithelial absorption. Similar to other epithelial tissues, the epithelium of the conjunctiva and cornea are capable of regulating the hydration status of the mucosal surface through active salt and water transport. The epithelial sodium channel (ENaC) regulates sodium and water absorption in numerous tissues, including the eye. The inhibition of ENaC in the eye is predicted to preserve lacrimal secretions and maintain hydration on the ocular surface. Parion Sciences has developed a novel series of compounds that specifically and potently inhibit ENaC, which are predicted to be good candidate molecules for clinical development for the treatment of dry eye. In a series of proof-of-concept studies, Parion’s lead compound, P-321, produced a concentration-dependent increase in tear output that persists with a long duration of action in normal mice and rats. Furthermore, P-321 significantly increases tear output and improves corneal staining in dry eye models. Taken together, these data suggest that ENaC inhibitors are excellent candidates for clinical development. Lead Collaborator Parion Sciences, Durham, North Carolina Karl Donn, Ph.D. Public Health Impact Keratoconjunctivitis sicca, or chronic dry eye disease, is one of the most frequently diagnosed ocular diseases, resulting in painful irritation, inflammation on the ocular surface and impaired vision. Parion Sciences is developing a novel therapeutic agent that may provide long-acting relief from dry eye symptoms. Outcomes Work on this project is complete. The investigators successfully filed an Investigational New Drug (IND) application using BrIDGs data and initiated clinical testing. Project Details Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies ND-directed toxicology Related Information News Brief: NEI Sets Stage for New Clinical Trial to Tackle Dry Eye ClinicalTrials.gov Listing: Study of the Safety and Tolerability of P 321 Ophthalmic Solution in Subjects With Dry Eye Disease | ||||||||
| 296 | 2013 Director’s Messages | Select a 2013 message from the list below: Feb. 26, 2013: Translation Is a Team Sport April 26, 2013: Partnering with Colleagues in Industry to Accelerate Therapeutics Development June 18, 2013: Translation in Three Dimensions: The 3Ds of NCATS Aug. 13, 2013: Exploring the Promise of Extracellular RNA Communication Sept. 12, 2013: Effective Preclinical Collaborations Enable Translational Innovations Oct. 22, 2013: Clinical and Translational Science Awards Catalyze and Speed Translational Research Dec. 17, 2013: Improving Health and Accelerating Drug Development Through Predictive Toxicology Feb. 26, 2013: Translation Is a Team Sport In the five months since I took over as NCATS director, I have visited with a wide variety of constituents who have a stake in what we do — patients, grantees, companies, and scientists and physicians across NIH and elsewhere — and it has become clear to me that many, perhaps most, do not fully understand what “translational science” is. This knowledge gap leads to mystification at best, and misconception at worst, about what NCATS is doing and will do. It is understandable in many ways; after all, NCATS is new and was designed to fill a critical need that complements the work of the other NIH Institutes and Centers. But for NCATS to be successful, our constituents must understand our science and mission. To that end, now and in the future, I will use recent examples of NCATS’ work to illustrate what translational science is and how it differs from the basic research and clinical medicine that flank it in the research ecosystem. One key feature of translational research is this: translation must be a team sport. Many of the greatest discoveries in fundamental laboratory research, and the best care of individual patients, are brought about by individuals who specialize in particular areas of science or medicine. I personally have been privileged to do basic research and provide clinical care. However, the translational process is so multifaceted that no one person, no matter how committed or talented, can succeed alone. I am a fan of sports analogies (apologies in advance), and I often say “fundamental research is like golf, but translation is like football.” Although all the players aren’t on the “field” at the same time, each of their contributions is critical for success. The winning team must have not only brilliant individuals but interdependent team players to score the “touchdown” of a new intervention that improves human health in a tangible way. This kind of teamwork recently enabled the creation of a brain-computer-interface technology that allows paralyzed patients to move a robotic arm using only their thoughts. This remarkable work, published in The Lancet and featured on CBS’ 60 Minutes, was possible only because of the contributions of many members of a diverse research team. The collaboration relied on help from four federal agencies ― NIH, the Department of Defense, the Department of Veterans Affairs, and the U.S. Food and Drug Administration (FDA) ― along with support by a private foundation, a private company and two academic research centers including the University of Pittsburgh, funded in part by NCATS’ Clinical and Translational Science Awards program. In another great example of teamwork, last month NIH launched a clinical trial to test a treatment for a devastating childhood neurological disorder called Niemann-Pick disease type C. This project moved from the laboratory to the clinic swiftly due to a collaboration of researchers in 10 different disciplines, from genetics to neurosurgery, and from four NIH Institutes and Centers, three academic institutions, several patient-oriented nonprofits and family support groups, and a pharmaceutical company. Scientists from NCATS’ Therapeutics for Rare and Neglected Diseases program contributed to and coordinated the team’s work. Simultaneously, NCATS-supported research teams are creating entirely new ways to make the therapeutic development process faster, cheaper and more accurate. For example, NCATS’ Tissue Chip for Drug Screening program has partnered with the Defense Advanced Research Projects Agency and the FDA to develop microfluidic systems using 3-D human tissues that more accurately will predict potential toxicities of new drugs, thus addressing one of the primary reasons that drugs fail in development. In each of these examples of NCATS’ ongoing efforts, we have sought not only to catalyze collaborative development of new interventions, but also to establish new technologies and paradigms that can be implemented broadly to improve the efficiency of the translational process for all. I look forward to sharing more of NCATS’ translational science achievements with you as we continue to evolve. Since our mission is fundamentally collaborative, NCATS also will be highlighting ways we can hear from you and how you and your organization can get involved. I look forward to working with all of our partners as we continue to re-engineer translational science to deliver life-saving interventions more quickly to more people. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences April 26, 2013: Partnering with Colleagues in Industry to Accelerate Therapeutics Development My previous Director’s Messages have emphasized that translation is a team sport, describing my ongoing discussions with leaders from academia, government, industry and patient advocacy groups. The feedback from these conversations helps NCATS focus its priorities on the areas of greatest need and build the teams necessary to solve complex translational science problems that can prevent and delay the development of health-improving interventions. Last year, NCATS reached out to the Biotechnology Industry Organization (BIO) for its advice on the top challenges and opportunities in therapeutics, device and diagnostics development. BIO leaders canvassed the organization’s members to identify the system-wide translational problems they find most difficult and most important for NCATS to address. Following are some of the recommendations that resulted, and how NCATS’ programs address each area of focus. Identify biomarkers that better predict how patients will respond to therapies. NCATS is working with disease experts in academia and industry and with the Food and Drug Administration (FDA) on ways to identify biomarkers, show how they can predict response to an intervention, and demonstrate their effective and efficient use in the regulatory approval process. Develop predictive preclinical efficacy and toxicity testing methods. The majority of drug candidates fail in early (Phase II) clinical trials because they don’t prove effective enough to treat a specific disease. But these candidates still can be a source for new medicines if researchers demonstrate that the drugs are safe in people. Finding other potential diseases to treat with these partially developed drugs is the goal for NCATS’ Discovering New Therapeutic Uses for Existing Molecules program — an alliance involving eight pharmaceutical companies. NCATS leads two federal collaborations designed to improve ways to predict how effective or toxic a potential drug might be in humans: The goal of the Toxicology in the 21st Century (Tox21) program, which includes collaborators from the FDA, Environmental Protection Agency and National Toxicology Program, is to develop data-driven protocols that predict which chemical compounds have the potential to disrupt processes in the human body that may lead to adverse health effects. NCATS’ Tissue Chip for Drug Screening program is a partnership with the Defense Advanced Research Projects Agency and the FDA. Through this program, researchers are developing 3-D human tissue models that mimic the structure and function of human organs. Once developed, researchers will use these models to predict whether a candidate drug, vaccine or biologic agent is safe and effective in humans in a faster, more cost-effective way than current methods. Improve patient recruitment, clinical trial design and the institutional review board (IRB) process. Patient recruitment, novel clinical trial design and IRB harmonization are three areas of focus for the Clinical and Translational Science Awards (CTSA) program that NCATS leads. Take a leadership role in working with the FDA to develop and validate novel approaches to drug development. From its inception, NCATS has worked closely with colleagues at the FDA across a wide range of regulatory science issues. For example, in both the Tox21 and Tissue Chip for Drug Screening programs, experts at the FDA help us explore how these technologies can be used to assess drug effects prior to approval for first-in-human clinical studies. I want to thank each of you in the academic, nonprofit, biotechnology, pharmaceutical and venture capital communities who have and continue to contribute time, experience and advice to help NCATS focus on the most pressing issues in translational science. I look forward to continuing these discussions with both current and new stakeholders so that NCATS can align its resources most effectively with the public and private sectors to speed scientific innovation and improve human health. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences June 18, 2013: Translation in Three Dimensions: The 3Ds of NCATS Much has been written about scientific and operational problems that limit our ability to develop and deploy new and effective interventions to improve human health. Much less has been written about potential solutions to these problems — and that’s where NCATS comes in. We focus on developing these kinds of system-wide solutions. However, we also know that a goal to develop technologies and models that might improve some aspect of the translational process is simply not enough. Rather, we must demonstrate that these solutions improve the efficiency or effectiveness of an intervention through real-world examples. And if we are successful, we cannot assume that others will adopt these new technologies; instead, we must disseminate the translational advances proactively so that the broader research community can understand, apply and benefit from them. To illustrate these principles, consider the Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) program. Today, NIH and NCATS announced the first project awards for this crowdsourcing effort to explore potential treatments in eight disease areas using existing pharmaceutical compounds. New Therapeutic Uses addresses several specific hurdles in the translational process: The urgent need for medicines to treat the several thousand known diseases that do not have effective therapies approved by the Food and Drug Administration (FDA). The large number of partially developed molecules that failed partway along the lengthy and difficult path to making a new medicine. The complicated process of negotiating agreements between parties that want to work together, particularly pharmaceutical companies and academic investigators. To address these obstacles, we seek potential solutions by gathering broad input about New Therapeutic Uses from across the research community (see the new Request for Information to submit your feedback). New Therapeutic Uses is an outcome of a meeting (PDF - 114KB) of NIH, pharmaceutical and academic leaders in 2011. The proposed approach was for NIH to serve as a matchmaker between pharmaceutical companies, which had molecules that were safe but not effective for their original disease target, and academic scientists, who had new ideas to use these molecules to fight other diseases. To realize this vision, NIH worked to develop (the first D) two components: (1) standardized template agreements to help NIH, academic scientists and pharmaceutical companies work together efficiently and (2) a mechanism to “crowdsource” ideas for new therapeutic uses from the broad academic community. To demonstrate (the second D) that academic-industry matchmaking was feasible and effective, NIH worked with eight pharmaceutical companies that volunteered compounds as test cases in the New Therapeutic Uses pilot program, launched in May 2012. The companies made detailed information on 58 molecules available on the NCATS website, and they committed to releasing needed data and supplying each compound at no cost to NIH or the investigators. Ultimately, nine proposals were chosen for funding and announced today. These awards, supported by the NIH Common Fund, go to investigators at academic institutions across the country. During the next two to three years, these scientists will collaborate with the pharmaceutical companies that developed the molecules to test new therapeutic uses in patients with common and rare diseases. When these studies are complete in the next few years, we will know if these ideas truly could become new treatments. But already this bold experiment has produced general insights that we can disseminate (the third D) to the research community to improve the translational process. By applying the 3Ds to the “wisdom of the crowd” in the New Therapeutic Uses program, NCATS has served as the crucial matchmaker for fundamentally new scientific partnerships to bring more treatments to more patients more quickly. Stay tuned for more exciting developments! Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Aug. 13, 2013: Exploring the Promise of Extracellular RNA Communication A major NCATS mission is to develop new technologies and models that scientists in many different fields can use to advance translational research and ultimately improve health. Given the enormous opportunities and needs in translational science, we are particularly interested in “game-changing” technologies that could revolutionize the field. Extracellular RNA (exRNA) communication, a recently discovered type of cell signaling, is one such new area. Scientists previously believed that RNA worked mostly inside the cell that produced it, but recent findings show that cells release certain types of RNA that travel through body fluids to affect other cells. ExRNA appears to have many functions in the body and may play an important role in health as well as in a wide range of diseases. Though still in its early days, exRNA looks to be another of those remarkable discoveries of a naturally occurring process that has enormous translational potential — like RNA interference (RNAi) and stem cells. Stem cells can renew themselves and transform into many different cell types, and they are being used in many of NCATS’ programs to develop drugs more safely and effectively. RNAi is a process by which the activity of genes can be selectively decreased; scientists use RNAi in the laboratory to study the effects of individual genes and are developing RNAi-based therapies, particularly for cancer. Here at NCATS, our program in genome-wide RNAi screening has developed new methods that are driving reliable large-scale studies of gene function and identification of new therapeutic targets. ExRNA appears to hold the same potential for transforming translational research, but scientists still know very little about its basic biology, functions and roles in disease. To address this need, NIH developed a new trans-NIH program funded by the NIH Common Fund called Extracellular RNA Communication. Today, NIH announced that it will award $17 million this year for 24 research projects designed to improve scientists’ understanding of exRNA and investigate its role in a variety of diseases, including many types of cancer, bone marrow disorders, heart disease, Alzheimer’s disease and multiple sclerosis. NCATS will administer 18 of these awards to develop biomarkers from exRNA found in body fluids and to create new therapeutic strategies for using exRNA in developing and delivering treatments. The ExRNA program also illustrates a point I make often, about the intersection of fundamental and translational research and how each benefits the other. Discoveries in basic science feed forward to translation, just as translational discoveries often illuminate fundamental mechanisms. ExRNA is both a type of cell-to-cell communication and a route to disease understanding, diagnostics, biomarkers and therapeutics. Like the DNA formerly known as “junk” (the DNA residing outside of genes that we now know has important functions), exRNA was formerly thought to be functionless cellular debris. There are undoubtedly many other such discoveries waiting to be made that will transform both our understanding of ourselves and our ability to intervene when things go wrong. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Sept. 12, 2013: Effective Preclinical Collaborations Enable Translational Innovations In an increasingly multidisciplinary research world, innovative scientific advances require effective collaborations. As I often say, translation is a team sport. These partnerships — among academia, government, industry and nonprofits — enable and speed the development of promising interventions to prevent and treat disease. Collaborations are especially important when it comes to developing treatments for rare and neglected diseases. Private companies may not pursue new therapies for these diseases because of the low anticipated return on investment. One way to lessen this scientific and financial risk — to “de-risk” a project — is to share the work with partners. NCATS’ Therapeutics for Rare and Neglected Diseases (TRND) program is designed to do just that. TRND creates research partnerships between NCATS scientists and academic investigators, nonprofit organizations, and pharmaceutical and biotechnology companies. These therapeutic development partnerships reduce the risks, time delays and costs of advancing treatments for rare diseases into the first stages of clinical testing. Once projects are “de-risked” to this stage, companies are more willing to adopt them and invest the still-considerable resources needed to complete development and achieve regulatory approval. We often think of TRND as a “bridge” to get rare and neglected disease therapeutics from the idea stage to the proof-of-principle stage. Another NCATS preclinical development program that uses a different collaborative model is, appropriately, named BrIDGs (Bridging Interventional Development Gaps). BrIDGs provides targeted contract access to drug development resources that allow academic, not-for-profit and small business collaborators to generate the data needed for an Investigational New Drug (IND) application to the Food and Drug Administration. Today, NCATS reaches two important milestones with these programs. First, NCATS is holding its first Research and Development Day in Cambridge, Massachusetts, showcasing projects and technologies from TRND and BrIDGs for an audience of biopharmaceutical companies, venture capitalists, angel investors, foundations and others interested in potentially adopting the projects and completing their development, manufacture and marketing. I am enormously gratified by the work that the TRND, BrIDGs and partner scientists have done to move the candidate treatments being showcased today much closer to use in patients — and to attract much interest from the biopharmaceutical community. With TRND and BrIDGs projects ready to “graduate” from NCATS at R&D Day, we accept four new projects into the TRND program today. NCATS selected the projects for their potential both to treat specific rare diseases and to help TRND scientists uncover new information that can be shared with researchers developing therapeutics for many other diseases. This group of projects also marks the TRND program’s first use of stem cells and its first collaboration with a large pharmaceutical company, Eli Lilly and Co., to co-develop a treatment for a rare disease. Two of the four projects involve innovative therapeutic approaches to developing a treatment for retinitis pigmentosa, a severe form of hereditary blindness. A third project focuses on a potential treatment for hypoparathyroidism, a syndrome that leads to a persistent lack of calcium and the need for high-dose supplements that can damage the kidneys. The remaining project involves development of a treatment for a heart disorder associated with LEOPARD syndrome, an extremely rare genetic disease that can lead to early death. With today’s milestones, NCATS moves one step further to achieving its mission of developing, demonstrating and disseminating new technologies and models that will transform the translational process and thus speed the delivery of more treatments to more people more quickly. Thank you for your interest, and I hope you will return to our website often to keep up with the exciting developments in all of NCATS’ programs and to partner with us in our work. We look forward to hearing from you. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Oct. 22, 2013: Clinical and Translational Science Awards Catalyze and Speed Translational Research In recent years, basic scientists have made breathtaking advances in our understanding of the human body’s biology and chemistry. The human genome has been sequenced, stem cells understood and RNA interference discovered. All of these advances have been celebrated for holding enormous promise for improving human health. But the road from promise to achievement of health impact — what is called “translation” in medical research terms — is long, complex and full of obstacles. For example, it can take 14 years or more before a basic discovery leads to a new treatment. Another decade can pass before that intervention is available to all patients who need it. Speeding up this process is a top priority for NCATS, and the Clinical and Translational Science Awards (CTSA) program is key to our efforts. The CTSA program supports a national consortium of medical research institutions that work together to improve the way clinical and translational research is conducted nationwide. CTSA institutions develop new tools, methods, resources and services that catalyze research progress. Because translation can’t happen without cooperation and collaboration across disciplines, CTSA institutions also lead training and career development for a new breed of team-oriented scientists and clinicians focused on translation. YouTube embed video: https://www.youtube.com/watch?v=thKbSdeHFe4 Right-click to download a transcript (1KB) The CTSA program is NIH’s largest single investment in clinical research. Today, NIH announced more than $79 million in fiscal year 2013 funding to support 15 CTSAs. The 2013 awards expand the CTSA Consortium to include Dartmouth College in New Hampshire, extending the program’s nationwide network to 31 states and the District of Columbia. NCATS is continuing to evolve the CTSA program to meet the needs of clinical and translational investigators and the communities they serve. In June 2013, the Institute of Medicine (IOM) issued a report of its findings following an in-depth review of the CTSA program. Its recommendations included formalizing and standardizing the evaluation processes for individual CTSA institutions and the program as a whole, advancing innovation in education and training programs, and ensuring community engagement in all phases of research. We already are making strides toward addressing these priorities. NCATS has assembled a working group of stakeholders to guide program changes and implement the IOM report’s recommendations. One of the group’s first tasks is development of clear, measurable goals and objectives for the CTSA program that speak to critical issues across the full spectrum of clinical and translational research. All of these efforts will no doubt strengthen the CTSA institutions, further enabling their leadership of national efforts to enhance the efficiency, quality and safety of translational research and the translation of scientific findings into interventions that improve human health. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Dec. 17, 2013: Improving Health and Accelerating Drug Development Through Predictive Toxicology We all are aware that chemicals can be helpful or harmful to our health, but the systems we have for evaluating those effects are, like so many aspects of translational research, inefficient and often ineffective. Chemicals can be more than just life-saving (e.g., penicillin) or life-ending (e.g., cyanide). Most frequently, chemicals can fall into either category, depending on the context and the dose. For example, the drug warfarin is effective both at preventing stroke in humans and at killing rats. Toxicity — a chemical’s ability to produce harmful effects in animals or humans — causes nearly one third of drug development failures and can produce harmful health effects from chemicals in the environment. Scientists cannot tell in advance whether a compound is toxic because they usually don’t know how it affects the molecules and cells of the body. If scientists could better predict which chemicals may be harmful, they could produce safer drugs and chemicals more quickly and efficiently. In this quest, NCATS partners with the National Toxicology Program at the National Institute of Environmental Health Sciences (NIEHS) and two other federal agencies in an initiative called Toxicology in the 21st Century, or Tox21. The collaborative effort began in 2008 among NCATS, NIEHS and the Environmental Protection Agency (EPA), with the Food and Drug Administration (FDA) joining in 2009. The program grew out of a 2007 National Academy of Sciences report, Toxicity Testing in the 21st Century: A Vision and Strategy, and a commentary in Science co-authored by NIH Director Francis S. Collins, M.D., Ph.D., which emphasized shifting toxicity testing from animals to tests called “assays” that use cells and biochemical components. This shift may improve scientists’ ability to predict toxic effects from chemicals more quickly and efficiently. (In addition to Tox21, NCATS’ Tissue Chip for Drug Screening program also is designed to improve toxicity testing.) Through the Tox21 program, researchers are testing 10,000 drugs and environmental chemicals for their potential to affect molecules and cells in ways that can cause health problems. The compounds undergo testing in the high-speed robotic screening system at the NCATS Division of Preclinical Innovation in partnership with our Tox21 collaborators at NIEHS, EPA and the FDA. One of the most effective ways to enable translational research improvements is releasing data to the public, so all Tox21 results are made available in the National Library of Medicine’s PubChem database as well as in public NIEHS and EPA databases. Today, EPA announced the release of new toxicity data on 1,800 chemicals from its ToxCast library, which is part of the Tox21 library of 10,000 chemicals. The scientific community can access this information on a new Chemical Safety for Sustainability Dashboard, a user-friendly, Web-based system. As part of this data release, the EPA is launching a data challenge, asking the scientific community for innovative ways to use the new data to predict negative health effects. Also this month, the Tox21 partners are celebrating winners of the program’s NIEHS–NCATS–UNC DREAM Toxicogenetics Challenge, which resulted in a greater understanding of how a person’s individual genetics can influence their body’s response when exposed to widely used chemicals. Tox21 is a great example of the NCATS approach to scientific and organizational problems in translational science. Scientifically, Tox21 researchers focus on improving toxicity testing across a broad diversity of drugs and chemicals to look for effects applicable to any organ system or disease. Organizationally, Tox21 is teamwork at its best: multiple federal agencies with complementary expertise tackling a complex chemical, biological and data-heavy challenge by leveraging existing resources. For example, NCATS scientists adapted one of the existing high-speed robots at the NCATS Chemical Genomics Center to test the Tox21 compounds. Strategies like these highlight how NCATS is developing, demonstrating and disseminating improvements in translational science, creating a whole that is greater than the sum of its parts. I hope you will follow the developments in these toxicity programs as they propel better treatments and better health. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences | ||||||||
| 295 | Development of HGF Mimetic (Refanalin) for Hepatic Fibrosis | Liver fibrosis is excessive accumulation of scar tissue in the liver. It can be the result of almost any type of chronic liver disease, or it can be congenital. It is generally progressive and, in advanced cases, can be life threatening, causing cirrhosis and liver failure and requiring a liver transplant. Liver fibrosis is also a risk factor for liver cancer. Definitive evaluation of liver fibrosis and determination of its cause requires an intrusive biopsy with severe pain in many cases and major complications in some. Current therapies are aimed at treating the underlying disease process, which may stop progression but usually does not reverse the fibrosis. These researchers are developing a treatment for liver fibrosis that works by opposing the genes that produce the scar tissue. This drug candidate also has the potential to reduce existing build-up and improve liver function. Scientific Synopsis Hepatic fibrosis affects millions of patients worldwide and remains an unresolved challenge for clinicians. Characterized by excessive accumulation of extracellular matrix proteins, including collagen, fibrosis is the common end-stage outcome in most chronic liver diseases. Left untreated, liver fibrosis progresses to cirrhosis and hepatic failure, a life-threatening condition necessitating liver transplantation. Currently approved therapies are aimed only at the underlying disease, with reversal of fibrosis occurring in a subset of patients over several years; for many other patients, there are simply no treatment options. Given the morbidity/mortality associated with this disease, there is an urgent need for translation of emerging antifibrotic modalities into effective therapies. Scatter factor/hepatocyte growth factor (SF/HGF) is a hepatotrophic factor that exerts antifibrotic effects by opposing TGFβ1 activity. Unfortunately, clinical feasibility of SF/HGF gene/protein therapy is compounded by numerous logistical and financial challenges. Together with Angion Biomedica Corp., we have developed Refanalin, a small molecule mimetic of SF/HGF, for treatment of liver fibrosis. Data from in vitro assays indicate that Refanalin opposes the hepatic fibrogenic gene program. In preclinical models of liver fibrosis, Refanalin is therapeutic, attenuating profibrotic gene and protein expression, accelerating collagen catabolism, and improving hepatic function. Refanalin has oral bioavailability and oral efficacy, and data from pharmacokinetic/acute safety studies indicate that it is safe and has properties consistent with a drug-like compound. In a chronic disease state requiring prolonged therapy, an orally efficacious drug is desirable. This is especially true in the liver, where first-pass metabolism optimizes hepatic delivery, minimizing extrahepatic effects. This application, designed to complete preclinical development of Refanalin, requests support from the program for GMP bulk synthesis, oral formulation and long-term toxicology studies. Together with the preclinical studies we conducted, the proposed studies are necessary and sufficient to support clinical trials of oral Refanalin administration in liver fibrosis. Lead Collaborators Icahn School of Medicine at Mount Sinai, New York , New York Scott L. Friedman, M.D. Efsevia Albanis, M.D. Public Health Impact Currently, no agents are approved as antifibrotic therapeutics in patients with chronic liver disease. At least 4 million Americans are infected with hepatitis C virus and up to 10 million may have obesity-related fatty liver associated with fibrosis (“non-alcoholic steatohepatitis,” or NASH); hundreds of millions worldwide are affected by these diseases. Outcomes Work on this project is complete. The investigators successfully filed an Investigational New Drug (IND) application using BrIDGs data and initiated clinical testing. Project Details Synthesis of Good Manufacturing Practice (GMP) material Development of an oral formulation Bridging study connecting previous and future toxicology studies Oral toxicology study with correlative pharmacology and histopathology | ||||||||
| 294 | Development of Assays to Detect Anti-Drug Antibodies Against ACP-501 | Familial lecithin:cholesterol acyl-transferase (LCAT) deficiency, also known as FLD, is a rare, inherited disease in which people have abnormally low levels of high-density lipoprotein (“good”) cholesterol. FLD causes vision problems, kidney failure and anemia. Patients with FLD have a genetic defect in LCAT, an enzyme required to make normal cholesterol. Currently, no approved treatment exists for FLD. The investigators have developed a man-made version of the natural LCAT enzyme as a replacement therapy for FLD. This project involves studying the effects of the potential treatment in mouse and human blood samples. Scientific Synopsis The objective of this project is to provide effective enzyme replacement therapy (ERT) using recombinant human LCAT for patients with inherited mutations in the LCAT gene. These mutations result in FLD. FLD patients have drastically reduced high-density lipoprotein (HDL) cholesterol levels and develop corneal opacities, anemia, proteinuria or renal dysfunction. Glomerulosclerosis, the major cause of morbidity and mortality in FLD patients, may lead to renal failure in the fourth or fifth decade of life and necessitate dialysis or kidney transplantation. The investigators produced rhLCAT and have obtained proof-of-principle data for ERT using LCAT-knockout mice, an animal model of FLD. They also have incubated rhLCAT in vitro with plasma from FLD patients, which resulted in the normalization of the lipoprotein profile. These data allowed them to obtain Orphan Drug Designation for rhLCAT for the treatment of FLD patients. The research team also has submitted an Investigational New Drug application to the Food and Drug Administration (FDA) for this indication. In response to the application, the FDA requested a multiple-dose phase I study in FLD-affected patients, followed by a long-term extension study in the same patients. The FDA also requested a six-month toxicology study in LCAT-deficient mice. To enable these studies, the investigators must systematically assess the risk of an unwanted immune response to rhLCAT. Regulations and guidelines have been established for the development of immunoassays that detect, quantify and characterize antibody responses to therapeutic proteins, such as rhLCAT. BrIDGs will provide resources and expertise for the design and optimization of such immunoassays to detect and characterize anti-LCAT antibodies from human and murine plasma samples. Lead Collaborator AlphaCore Pharma, LLC, Ann Arbor, Michigan Brian R. Krause, Ph.D. Public Health Impact FLD occurs in individuals with a defective gene responsible for expressing the enzyme LCAT. The disease is characterized by cloudy corneas, anemia and eventually failure of the kidneys. AlphaCore Pharma is developing a form of LCAT, manufactured by biotechnological processes, to stop the loss of kidney function. Outcomes MedImmune, part of AstraZeneca, acquired AlphaCore Pharma in 2013 and accepted responsibility for the completion of this project. Project Details Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies | ||||||||
| 293 | Developing SRX246 for Stress-Related Affective Illness | Stress-related affective illness is the collective term for emotional illnesses caused by chronic stress, such as anxiety and depression. Long-term stress leads to many physical, behavioral, mental and emotional health problems. These stress effects on the human body are caused when the generalized physiological response to stressors is constantly turned on. This “fight-or-flight” response happens because of a cascade of hormones released when the hypothalamus receives the stress signal and passes it along to the pituitary and adrenal cortex. As many as 40 million Americans have symptoms of anxiety and depression, resulting in varying levels of debility. These researchers are developing a treatment for depression and anxiety. The new therapy operates by blocking a hormone called vasopressin that drives the hypothalamus-pituitary-adrenal cortex response to chronic stress. Scientific Synopsis A compelling case for the potential utility of vasopressin (AVP) antagonists as a novel therapeutic class for the treatment of stress-related affective illness has emerged based on observations in depressed individuals, findings in animal models of anxiety and depression, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. This proposal seeks support for the continued development of SRX246.HCl, a novel vasopressin 1a (V1a) receptor antagonist that has shown efficacy in preclinical animal models of anxiety and depression, good plasma bioavailability and CNS penetration following oral administration, a strong safety profile, and high affinity and selectivity for the target receptor. The scientific bases for V1a antagonists as a pharmacotherapy for anxiety and depression include (1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of anxiety and depression; (2) recognition that AVP, not CRF, drives HPA function associated with chronic psychological stress; (3) the CNS localization of V1a receptors in limbic system regions involved in HPA regulation and control of social behaviors; and (4) preclinical data with SRX246 showing efficacy in animal models employed as screens for anxiolytic/antidepressant activity. The public health need for new pharmaceutical treatments for stress-related affective illness is well documented. Existing pharmacotherapies for both indications are not uniformly effective and frequently have undesirable side effects. These limitations demonstrate that a new treatment approach through V1a receptor antagonism may offer significant opportunities for improved outcomes. Lead Collaborator Lehigh University, Bethlehem, Pennsylvania Neal G. Simon, Ph.D. Public Health Impact Anxiety and depression affect more than 40 million Americans each year and carry a conservatively estimated annual total economic burden of $125 billion. BrIDGs support for SRX246 will complement existing investments and significantly advance the likelihood of additional private sector investment to accelerate the commercialization of this agent. Outcomes The investigator successfully filed an Investigational New Drug (IND) application using BrIDGs data and initiated clinical testing. SRX246 eventually entered Phase II clinical trials in patients with intermittent explosive disorder. Project Details Synthesis of Good Manufacturing Practice (GMP) material Formulation development Investigational New Drug (IND)-directed toxicology |
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