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| 8834 | Strategic Goal 2: Advance translational team science by fostering innovative partnerships and collaborations with a strategic array of stakeholders. | Translating a basic discovery to a demonstrated improvement in public health requires a translational research team of scientists, clinicians, research participants and other stakeholders having a wide range of expertise and perspectives of the scientific and operational roadblocks. Progressing through the phases of the translational science spectrum requires the creation of productive and mutually beneficial collaborations that depend not only on individual excellence, but on teamwork, coordination, cooperation and communication. Partnerships and collaborations across individuals and organizations are essential because the expertise, capabilities and viewpoints required for successful translation tend to reside in different groups with distinct missions. For example, developing a potential therapy to the point of regulatory approval can require expertise in molecular biology, medicinal chemistry, compound synthesis and formulation, pharmacology and toxicology, technology transfer, clinical science, regulatory science, integrating patient perspectives, and entrepreneurship, among others. However, incentive structures and professional and cultural barriers can make teamwork difficult to navigate. For this reason, NCATS places high value on innovation in team science and partnership development, and designs and tests novel partnership structures that cut across traditionally siloed scientific disciplines, organizations and sectors. Successful approaches are shared for all in the biomedical research community to use to improve their own translational efforts. Additionally, NCATS recognizes that translation is a global effort and therefore engages in partnerships and collaborations with international entities in multiple sectors. | Translating a basic discovery to a demonstrated improvement in public health requires a translational research team of scientists, clinicians, research participants and other stakeholders having a wid | /sites/default/files/strategic-plan_900px.jpg | Strategic Goal 2: Fostering Innovative Partnerships | Translating a basic discovery to a demonstrated improvement in public health requires a translational research team of scientists, clinicians, research participants and other stakeholders having a wid | /sites/default/files/strategic-plan_900px.jpg | Strategic Goal 2: Fostering Innovative Partnerships | ||
| 8833 | Strategic Goal 1: Conduct and support innovative research that uncovers fundamental scientific and operational principles of translational science to catalyze the development and dissemination of novel medical interventions. | NCATS is fundamentally transforming how translation is conducted on a system-wide level through research in translational science that uncovers, characterizes and implements the scientific and operational principles underlying each step of the translational process. By developing new approaches, technologies, resources, and methods that transcend a particular discipline or single disease, NCATS empowers the entire biomedical research community to conduct translation more efficiently. NCATS will identify and develop additional scientific and operational innovations to overcome system-wide bottlenecks in translational research and deliver health benefits more quickly. | NCATS is fundamentally transforming how translation is conducted on a system-wide level through research in translational science that uncovers, characterizes and implements the scientific and operati | /sites/default/files/strategic-plan_900px.jpg | Strategic Goal 1: Conduct and support innovative research that uncover | NCATS is fundamentally transforming how translation is conducted on a system-wide level through research in translational science that uncovers, characterizes and implements the scientific and operati | /sites/default/files/strategic-plan_900px.jpg | Strategic Goal 1: Conduct and support innovative research that uncover | ||
| 8832 | 2018 Director’s Messages | Select a 2018 message from the list below: Jan. 2, 2018: Innovations to Increase Participation in Clinical Research Feb. 1, 2018: Patients Are Key to Rare Disease Day at NIH March 5, 2018: A New Map to Guide and Improve Therapeutics Development April 5, 2018: Practice Makes Perfect — “Good Clinical Practice” Makes Perfect Sense for Researchers May 1, 2018: Advancing Chemical Testing for the 21st Century June 6, 2018: Translating Translation July 10, 2018: Bringing Translational Science to the Opioid Crisis Aug. 1, 2018: Cross-Cultural Experiences Spark Advances in Translational Science Sept. 5, 2018: The Translational Science of Changing Behavior Oct. 3, 2018: Engaging Communities for Smarter Science Nov. 1, 2018: A New Portal for Creating “Inxights” in Drug Discovery Dec. 6, 2018: Team Science Champions! Jan. 2, 2018: Innovations to Increase Participation in Clinical Research Every person with an illness wants the best treatment available, and given the pace of biomedical research, that best treatment may be new or even still under study. And Americans are well-known for their attraction to the “new!”, believing that new likely means better. It is curious, therefore, that only a small number of people with any disease — generally less than 10 percent — participate in clinical trials of new treatments. This lack of participation greatly increases the time and cost of clinical testing of new interventions and regularly delays or prevents new treatments from being approved. One particular issue, given the increasing diversity of the U.S. population and the advent of precision medicine, is our inability to enroll enough diverse participants to adequately represent the U.S. population or the subpopulation for which an intervention is being developed. Too often, an investigator simply cannot find enough volunteers who meet the trial criteria and must either find additional resources to boost study recruitment efforts or cancel the study. Put simply, our increasing recruitment failures threaten to choke off translational progress. As a result, NCATS has designated recruitment innovation as one of its top priorities. A centerpiece of our efforts is the Clinical and Translational Science Awards (CTSA) Program’s Recruitment Innovation Center (RIC), a part of the CTSA Program Trial Innovation Network. Researchers at the RIC, which is based at Vanderbilt University with connections to all the CTSA Program hubs, are developing and disseminating best practices for engaging and recruiting participants, particularly from communities traditionally underrepresented in clinical research. Through the CTSA Program’s Accrual to Clinical Trials (ACT) initiative, researchers are forming a national network of sites that will use electronic health record (EHR) data to identify potential participants. Since health care systems vary widely in how their EHR data are organized, searching across institutions for eligible patients has been a persistent challenge. ACT investigators are working with widely used open-source technologies to enable a qualified researcher to search for eligible participants while protecting patient privacy and meeting all legal and ethical requirements. I also am excited about the Strengthening Translational Research in Diverse Enrollment (STRIDE) initiative, a collaboration among three CTSA Program hubs to develop and test innovations to increase participation of underrepresented groups, including African Americans and Latinos, in clinical trials and other research efforts. STRIDE tools will include culturally, linguistically and literacy-tailored recruitment and informed consent protocols. Once the innovations are shown to be effective, STRIDE investigators will disseminate the tools broadly so that anyone can use them to improve recruitment diversity for clinical trials and other translational research. Through these and other efforts to increase participation in research, NCATS is both accelerating translation and ensuring that its benefits reach all who need them. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Feb. 1, 2018: Patients Are Key to Rare Disease Day at NIH There are about 7,000 diseases officially defined as “rare,” or affecting fewer than 200,000 people in the U.S.; only a few hundred of these diseases have any approved treatment. Added together, these disorders are anything but rare: They affect 25 million people in the U.S., and approximately 50 percent of these patients are children. Most clinicians go through their entire careers without seeing a patient with one of these rare diseases; thus, patients and their families struggle first to get an accurate diagnosis, and then to get proper care and treatment, all while coping with frequently debilitating and costly illnesses. NCATS is deeply engaged in finding breakthrough approaches to all aspects of this urgent and oft-neglected problem. One of the approaches we feel has the most potential is to turn the usual paradigm of diagnostic and treatment development on its head, by putting the ultimate consumers of these products — patients and their families — at the head of the line of consideration in research projects, versus at the end. For many reasons, patients have traditionally been brought into the translational projects late in the process; not surprisingly, this has led to interventions that are not well-suited to the needs and realities of actual patients — and, ultimately, to translational failure. As one of my first directives as NCATS director, I therefore exhorted the Center’s scientists to involve patients in every project we do, to test the hypothesis that such involvement will make translation more relevant and effective. I am glad to report that NCATS now partners with patients and their caregivers and advocates at every stage of the translational science spectrum, with the goal of not only improving research efficiency and effectiveness, but also developing “best practices” for patient involvement in translational research — that is, a translational science of patient engagement. Patients were principal drivers in the construction of the NCATS Toolkit for Patient-Focused Therapy Development. They also partner with the Rare Diseases Registry, or RaDaR, Program to build registries to increase understanding of the characteristics and progression of a disease, improve the design of clinical trials to study a disorder, and help select meaningful study endpoints to evaluate. To increase public and research community awareness of these disorders, we have promulgated the perspectives of individual patients, such as Alani Daniels and Marcela Ferrada. Our “patients first” approach will be on display March 1 of this year during Rare Disease Day at NIH, which is co-sponsored by NCATS and the NIH Clinical Center. “Patients and Researchers — Partners for Life” is the guiding principle for NIH’s annual event that connects patients and their support groups with scientists, clinicians and policymakers to discuss collaborative research efforts that are making a difference. Based on feedback from last year’s participants, we are incorporating new formats that facilitate greater audience participation. If you are able to travel to the NIH campus in Bethesda, Maryland, for this event, please register here; if you are unable to join us in person, please join us via webcast. Most important, know that every day is rare disease day at NCATS. For example, our support helped the Primary Immune Deficiency Treatment Consortium, part of our Rare Diseases Clinical Research Network, address the high incidence of a genetic condition in the Navajo Nation. In addition, through our Therapeutics for Rare and Neglected Diseases program, we collaborated to advance a new gene therapy for a muscle disorder. Learn more about NCATS’ work in all aspects of rare diseases research by viewing our newly released video. See you on March 1! Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences March 5, 2018: A New Map to Guide and Improve Therapeutics Development Anyone embarking on an unfamiliar journey will want a map to help plan needs, anticipate problem spots and formulate contingency plans. This is all the more true if the journey being contemplated is known to take many years, be fraught with hazards and rarely be completed successfully. In this case, one would want a very good map indeed, one that could both guide new travelers and assist construction engineers in improving it. The drug development process is such a journey, taking decades from idea to patient, during which hundreds of attempts fail and enormous costs are borne. The common moniker of a drug development “pipeline” is wildly and tragically misleading, implying as it does a simple and inevitably successful path from a laboratory observation to an available therapeutic. The pipeline misnomer engenders improbable expectations among patients, scientists, physicians, and policymakers and impedes efforts to improve the therapeutic development process. NCATS took on the creation of a new and accurate map as central to our mission to develop solutions to translational roadblocks and disseminate them for use by the research community. I am glad to report that an exciting new map has now been produced and is publicly available on our website. In true NCATS fashion, we partnered with academics, pharmaceutical and biotech companies, regulators, foundations and patient groups to create the map under the auspices of a component of the National Academies of Sciences, Engineering, and Medicine. This Drug Discovery, Development and Deployment Map, or “4DM,” was described in two recent pieces in Nature Reviews Drug Discovery and Clinical and Translational Science. Even the casual observer will note that the 4DM is complicated, with different phases, termed “neighborhoods,” and multiple steps within and between neighborhoods that may need to be attempted multiple times before success occurs. But a truly useful map not only indicates routes, it enables travelers to anticipate problem spots. So like the ubiquitous smartphone apps for road traffic we all use, the 4DM has a crowdsourced feature that indicates the steps in the process that previous drug developers have found particularly prone to failure, delays or high cost. Like road engineers, NCATS will use this “traffic” feature to focus our translational re-engineering efforts on the most problematic steps of the process. In this initial version, the 4DM is static, but we have already begun developing additional features to make the map interactive. For example, future versions will enable users to locate their translational project on the map via a “GPS” feature based on answers to a series of questions, allowing them to identify next steps and options to best advance their efforts. We’ll also be adding connections to NCATS resources to help users through these steps. These resources include our Therapeutics for Rare and Neglected Diseases program for preclinical studies and our Clinical and Translational Science Awards Program in the clinical and implementation domains. The 4DM is available under a Creative Commons license, so anyone in the world can download, adapt and display it for their own use. Please use the map and give us feedback on what features we should add next to make it even more useful. I hope you will find the 4DM to be as helpful as we have for education, planning, engineering and ultimately increasing successful outcomes in the translational journey. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences April 5, 2018: Practice Makes Perfect — “Good Clinical Practice” Makes Perfect Sense for Researchers Given that translational science is such a young and growing field, NCATS places emphasis on training and workforce development. Until very recently, no one — myself included — trained to be a “translational scientist,” since the discipline did not exist. Translational science shares this characteristic with other new and exciting fields, such as data science. I have previously written about NCATS’ extramural and intramural trainee programs, our Assay Guidance Manual, Toolkit for Patient-Focused Drug Development, and international educational efforts, all of which aim to give those new to translational science the knowledge and skills they need to be contributors to the translational team. As readers of this column will know, studies of diseases and treatments in people are the lynchpin of translation but present many scientific and logistical challenges that are currently limiting efficiency and effectiveness. One reason for the persistence of these challenges has been the heterogeneity in practices of investigators conducting studies in humans. To tackle this issue, NCATS Clinical and Translational Science Awards (CTSA) Program investigators, led by the University of Michigan, collaborated to enhance, streamline and standardize training in clinical research processes across the consortium. These research processes are termed “good clinical practice” (GCP) by analogy to established standardized processes for the research laboratory (“good laboratory practice,” or GLP) and manufacturing (“good manufacturing practice,” or GMP). GCP is an international ethical and scientific quality standard for the design, conduct, recording and reporting of clinical studies. These common standards can help ensure the integrity of the data collected, which in turn boosts confidence in research results. The CTSA Program GCP team identified a need for training that addressed the unique aspects of clinical trials for behavioral interventions. Behavioral trials tend to pose lower risk to participants and are not regulated by the U.S. Food and Drug Administration. But they can be more complicated, taking place in a range of settings outside the clinic, such as in schools and homes or even online, where investigators have less control over the research environment. In addition, behavioral trials can be administered by personnel with a variety of backgrounds, from clinicians to social workers to community leaders. Some aspects of traditional GCP training were not relevant to behavioral research, while other unique issues were not covered at all. To solve this systemic problem, the CTSA Program team developed an e-learning course that applies GCP principles to social and behavioral research. The course was initially disseminated throughout the CTSA Program consortium, and it is now available through the NIH Office of Behavioral and Social Sciences Research. It has been adopted by professional organizations such as the Society of Behavioral Medicine and by the NIH Common Fund’s Science of Behavior Change program. Moreover, the Collaborative Institutional Training Initiative, a leader in certifying researchers in GCP, has now integrated the training into its offerings. GCP certification is now required for every investigator and coordinator working on an NIH-funded study involving human participants. The GCP project is a notable example of NCATS’ “3 Ds” in action. We supported development of the GCP training for behavioral intervention trials as well as testing to demonstrate its usefulness, and we have disseminated the training broadly to the social sciences and behavioral research community. I invite you to learn more about all our clinical research tools that are helping to improve health through smarter science. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences May 1, 2018: Advancing Chemical Testing for the 21st Century “Chemicals” are sometimes thought of as being universally detrimental to health, with the possible exception of “natural” chemicals. In fact, the word “chemical” describes a vast universe of millions of molecules, both naturally occurring and man-made, that can have beneficial effects (like penicillin or vitamin C) or toxic ones (like carbon monoxide or dioxin). Further, most chemicals — even pure water — can be toxic if consumed in large enough quantities. Our inability to predict whether a new chemical might cause adverse health effects at doses people are normally exposed to is one of the greatest causes of translational failure in drug development and uncertainty in environmental health. Remarkably, our methods for evaluating the safety (or its opposite, toxicity) of chemicals have changed little over the past 50 years due to technical barriers and appropriate caution about protecting public health. But beginning about 10 years ago, this began to change as NIH and several other federal agencies joined together in an unprecedented collaboration to drive toxicity testing into the 21st century. This ambitious vision required better methods to rapidly and efficiently evaluate the safety of environmental chemicals, pesticides, food additives and drugs. Established in 2008, the Toxicology in the 21st Century (Tox21) program became part of NCATS when our Center was launched in fiscal year 2012. Through the program, scientists have developed and validated new high-throughput screening assays (tests) and generated and made public data on tens of thousands of chemicals; for many of them, there had been no information about potential toxic side effects. These data are now beginning to inform regulatory decisions about safety. Tox21-supported advances are remarkable and have transformed how chemicals are evaluated for their potential effects on human health. But the work is just beginning, since these successes also have enabled a greater understanding of key obstacles that must be overcome to achieve our original vision. These roadblocks include technical and biological limitations of current methods, as well as barriers to efficiently translating screening results into regulatory decision making. To address these challenges, Tox21 partners from NCATS, the National Toxicology Program at NIH’s National Institute of Environmental Health Sciences, the Environmental Protection Agency, and the Food and Drug Administration have released a new strategic and operational plan that expands the program’s research activities. The plan shifts Tox21’s primary focus from screening libraries of chemicals to follow-up studies that address specific focus areas, using a new type of cross-partner project. There are many examples of how discoveries from Tox21 are informing new research directions. For instance, in a previous message I discussed how Tox21 scientists had screened cells from a group of genetically diverse people and demonstrated that individual responses to many chemicals varied much more than previously thought. One of the five new focus areas for Tox21 will address genetic variability between different groups of people by creating alternative test systems. This approach could further improve the predictive power of chemical evaluations and identify populations that are especially susceptible to certain substances. Tox21 is just one example of NCATS’ success in developing entirely new paradigms that are making translation more efficient and effective through collaboration, new operational models and smarter science. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences June 6, 2018: Translating Translation NCATS is unique at NIH in that the name in the Center’s mission — “translation” — has a firmly established meaning that is generally associated with languages, not biomedical research. By contrast, other NIH components are named for widely known medical problems, such as cancer, diabetes and stroke. NCATS’ outreach and education efforts are therefore especially complex. First, we must define what “translation” means as a biomedical research term. Second, we must convey why it matters. And third, we must explain what NCATS is doing to improve it. To understand NCATS’ definitional challenge, imagine for a moment that neither you nor anyone you know, including your scientist and physician friends, had ever heard of cancer. But you knew it to be an enormous and deadly problem, and you were working hard to find a cure for it. You would have a difficult time garnering interest in your work until your colleagues understood what “cancer” was. Substitute “translation” for “cancer” and you can better understand NCATS’ challenge as well as its potential. To help bridge this gap, I recently published a brief about three related terms — translation, translational research and translational science — in Nature Reviews Drug Discovery. I hope you will take a look at this freely available commentary and send me feedback. “Translation” is firmly established as meaning the conversion of a message from one language into another. Biomedical translation, by analogy, is the process of converting a scientific or clinical observation into an intervention (e.g., drug, device, surgical procedure, behavioral change) that is shown to improve health. Scientific translation is an exceedingly complicated process that involves dozens of steps. (See our Drug Discovery, Development and Deployment (4DM) Maps for a glimpse of just how complicated translation can be.) Imagine the child’s game of “telephone,” in which a message is translated into one person’s language, and then another, and so on a dozen or more times. The likelihood that the original meaning of the message would be successfully delivered in the final person’s language would be very small. Welcome to the world of biomedical translation! The definitions of “translational research” and “translational science” follow from this understanding of the meaning of translation. Translational research attempts to move a particular project across one step of the translational process. In our telephone game analogy, translational research would correspond to the attempt to accurately convert a message from one language to another language (e.g., English to Chinese). By contrast, translational science is the quest to understand how the translational process works, both at each step and as an integrated whole, so that we can improve the process to work faster and more successfully. In our telephone game, this would correspond to the study of what languages have in common, why individual translational steps fail, how to make those steps more reliable and whether it is possible to skip certain steps altogether. Why do so many drugs that are safe and effective in animals turn out to be toxic in humans? How could lab tests give better, more accurate answers about whether a new drug will work? How could clinical trials in humans be conducted more efficiently and safely? These are some of the translational science questions NCATS is trying to answer. Understanding these definitions leads to rethinking the fundamental biomedical challenge of our era: how to deliver on the promise of science for patients in need. I will explore this reconceptualization, and its implications for NCATS, in upcoming messages. Stay tuned! Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences July 10, 2018: Bringing Translational Science to the Opioid Crisis Every 13 minutes in the United States, a person dies from an opioid overdose. The number of these overdose deaths — more than 42,000 in 2016 — continues to rise dramatically, paralleling the rise in deaths from HIV/AIDS during the height of that epidemic. Opioid-induced death is a public health crisis of historic proportions, with devastating consequences for individuals, families, communities and the nation. Opioid addiction is a complex problem that will require medical, social, legal and community solutions. But research also has an important role to play in understanding the underlying biology of addiction and pain, developing new interventions to treat them, and determining which interventions are most effective. This past April, NIH launched an innovative research agenda called the HEAL (Helping to End Addiction Long-term) initiative, focused on two critical areas: improving treatments for opioid misuse and addiction, and finding non-opioid approaches to pain management. Over the past year, I have been working closely with my NIH colleagues to apply NCATS’ translational science approach to the HEAL initiative. The opioid crisis typifies the translational challenge at every step, from validation of new targets to development of innovative treatments and clinical trial end points to recruitment for clinical studies, which is particularly difficult since the population is stigmatized and may be in legal jeopardy. And even when new interventions demonstrate effectiveness in controlled clinical trials, their uptake in medical care settings is often low, limiting their dissemination to patients in need. This problem was the focus of a study published last month on medication-based treatment after opioid overdose. With support from NCATS’ Clinical and Translational Science Awards Program, investigators found that only a fraction of individuals who would likely benefit from medications to treat opioid use disorder receive them after surviving an overdose. NCATS is bringing our unique approach to bear on these many challenges. Through the HEAL initiative, we are leading a trans-NIH effort to develop innovative, human cell-based screening platforms and novel drugs to treat opioid misuse, addiction and pain. Our efforts will tap into many of NCATS’ existing efforts, including induced pluripotent stem cells, 3-D Tissue Bioprinting and Tissue Chips for Drug Screening. We will use these innovative platforms to identify drugs that will undergo preclinical development via our NCATS Chemical Genomics Center and the Bridging Interventional Development Gaps and Therapeutics for Rare and Neglected Diseases programs. We are planning similarly ambitious and innovative efforts in the clinical development and implementation of new opioid misuse/addiction and pain interventions, and I look forward to sharing more with you in a future message. Through the HEAL initiative, NCATS will demonstrate the breakthrough potential of translational science to address the public health challenge of our era. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Aug. 1, 2018: Cross-Cultural Experiences Spark Advances in Translational Science Training in scientific research and medicine tends to become increasingly specialized as it progresses, producing scholars whose deep knowledge of particular areas enables them to make unique discoveries in their fields. But these individuals are less well prepared for the cross-discipline “team sport” of translational science. In contrast, NCATS’ training initiatives emphasize a working knowledge of the many fields that are required for successful translation, and mastery of at least two of them. Experiences in new disciplines or different environments illuminate the needs and perspectives of partners in the translational science spectrum and foster fresh ideas that lead to novel approaches. This can be as simple as crossing campus to work with someone in a different scientific field, or as extreme as crossing an ocean to collaborate on studies in a distant land. The latter is the case for several Ph.D. scholars who are splitting their time between laboratories at NCATS and research institutions overseas. One student, Dorian Cheff, aims to accelerate research on treatments for an aggressive form of brain cancer. The training program enables her to learn assay design and high-throughput screening from NCATS scientists as well as disease biology knowledge from her mentor at the Karolinska Institutet in Sweden. Along the way, Cheff is also experiencing different mentoring styles and laboratory cultures, which will make her a more skillful leader and collaborator. Researchers can also experience different cultures by working for a period of their training in another part of the translational ecosystem, such as the biotechnology/pharmaceutical industry, regulatory agencies or patient organizations. A shining example of this approach is the Eli Lilly externship program, now in its third year, which is a fully immersive six-month experience at the pharmaceutical company Eli Lilly. This program is open to NCATS Clinical and Translational Science Awards Program trainees and researchers. Earlier this year, Josephine Taverna, M.D., reported on her Lilly externship experience, during which she helped develop computer models to guide drug development for Alzheimer’s disease. Taverna eloquently expressed her newfound appreciation for the challenges of developing a drug and the critical role of industry in developing new medicines for patients. After her presentation, I was delighted when Taverna posed a question back to my NCATS colleagues and me: “How can we better integrate academia and industry to overcome seemingly insurmountable barriers to efficient drug development?” The experience of Taverna and other NCATS externs in both sectors will empower more effective integration, and I encourage every aspiring and current translational scientist to have an externship experience. I have yet to speak to any translational scientist who does not consider their time in another sector or discipline as being transformative to their science and their career. To facilitate this becoming the norm for translational scientists, NCATS has developed new Training and Education web content that consolidates many of the Center’s education and training activities and resources, both those based here at NCATS and those at our translational science partner institutions. I hope you will check it out and learn how externships are making translation more relevant, efficient and successful. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Sept. 5, 2018: The Translational Science of Changing Behavior Behaviors such as physical inactivity, smoking and unhealthy eating have an enormous negative influence on health. Although unhealthy behaviors can lead to chronic disease, healthy behavior changes can be part of successful disease treatments. But making lasting behavior change is difficult, so translational scientists seek to understand, develop and implement more efficient and effective behavioral interventions, just as they do for the development of drugs, devices and medical procedures. The Science of Behavior Change (SOBC) program, which is supported through the NIH Common Fund and contributed to by NCATS, is taking a new and exciting approach to behavior change. Utilizing concepts from preclinical translation and drug development, behavioral scientists work to identify a target, develop assays (tests) to measure activity related to that target, and then study target activity in response to interventions. But rather than being molecular entities like proteins or genes, in behavior change research, the targets are the psychological processes and mechanisms that drive behavior. These include self-regulation, stress reactivity and stress resilience, or interpersonal and social processes. For example, a measure of self-regulation is “delay discounting” — the degree to which a person chooses a small reward immediately (e.g., one more cookie) instead of a larger reward later (e.g., weight loss). Stress responses and stress recovery times are measures of stress reactivity and resilience. Using this approach allows translational researchers to not only test whether a behavior change intervention worked, but also why it worked — or did not. Measures of target mechanisms that have been developed and validated by SOBC researchers, whether those measures are self-report assays, neuroimaging studies, physiological responses or behavioral assays, are freely available for use by others through the SOBC Measures Repository. This repository currently includes 113 measures in the areas of self-regulation, stress reactivity and resilience, and interpersonal and social processes. Beyond its potential to make the development of behavioral interventions to prevent and treat disease more efficient and effective, this work promises to inform NCATS’ efforts to improve medication adherence and to advance the science of dissemination and implementation of interventions shown to improve health. Now about that cookie… Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Oct. 3, 2018: Engaging Communities for Smarter Science At NCATS, we strive to engage many different types of communities throughout the translational science process, from laboratory discoveries to better treatments for disease to improvements in public health. Success along the way requires innovation, including new kinds of partners who bring different perspectives and skill sets, as well as nontraditional and often unconventional approaches. Identifying a problem is a first step. For example, researchers have long understood the dangers of high blood pressure and that taking certain medications can help keep this condition under control. But getting patients to take a daily medication — or even to see a doctor about their high blood pressure in the first place — is surprisingly difficult. What’s also known is that black men are more likely to die from complications of high blood pressure than any other demographic group in the U.S. Accordingly, researchers at the Smidt Heart Institute at Cedars-Sinai and the University of California, Los Angeles (UCLA) Clinical and Translational Science Institute (CTSI), an NCATS Clinical and Translational Science Awards Program hub, are working on a better way to reach these at-risk men by connecting them to health care in barbershops. The researchers knew that barbers tend to be trusted influencers in black male communities, that these barbers tend to see their clients much more often than their customers see a doctor, and that some patrons actually never visit a medical professional. What would happen if pharmacists went to the barbershops to evaluate and provide needed medication for patrons with high blood pressure? The UCLA CTSI Community Engagement Unit helped the research team find local barbers who agreed to assist with identifying study participants, and the scientists were soon on their way to learning more. Results showed that after six months, the men who met with pharmacists in their barbershops had significantly lower blood pressure. This demonstrated that the barbershop is an effective way to reach black men with health-related messages, and it also showed the value of pharmacists as members of the care team. One barber became so involved that he even served as a co-author on the study report published in the New England Journal of Medicine. What a great example of how community engagement can help reach people at risk, address a health disparity and even strengthen connections within the community! We shared and advanced other approaches to community engagement recently during our second annual NCATS Day, which this year provided a forum for participants to share and reflect upon patient and community needs as well as best practices for addressing those needs. Participants learned strategies to broaden participation in research and to incorporate diverse patient and community input into their work. The lively and informative discussion helped advance ideas for more collaboration and innovation in this critical area. Effective patient and community engagement is a central part of NCATS’ work to advance translational science to get more treatments to more patients more quickly. I look forward to sharing more with you as our efforts continue to expand and evolve. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Nov. 1, 2018: A New Portal for Creating “Inxights” in Drug Discovery Efficient translational research typically requires access to a myriad of data, but often the information translational scientists need most is located in many different places and may not be publicly or freely available. For example, an investigator might be developing a potential new drug without knowing that the approach had already failed in clinical trials, because those results were never published. Conversely, the approach might work, and a drug that acts on the same molecule in the body and could be repurposed might already exist. A lack of access to reliable, curated drug development information can mean wasted time, money and even lives. At NCATS, we seek to overcome scientific and operational problems that delay the translation of research discoveries into new treatments for patients. In the case of data access, a science-driven problem has led us to create an operational solution. This year, we launched NCATS Inxight: Drugs, an online portal that aggregates reliable, curated drug development data from multiple existing sources, all in one place. This user-friendly resource incorporates a substantial amount of manually curated data from multiple independent public sources, including data from the Food and Drug Administration (FDA). The inclusion of this previously unpublished FDA data was made possible through another collaboration with that agency: The FDA’s Substance Registration System was built on software developed at NCATS through the ginas project. NCATS Inxight: Drugs is the only biomedical resource to use a complete list of rigorously defined drug substances as its core dataset. The portal includes data for all U.S.-approved prescription and over-the-counter drugs, U.S.-withdrawn drugs, drugs marketed globally, and investigational interventions. Many of the drug profiles include referenced data on the method of action, targets, and uses (approved and off-label), information that can spark new scientific hypotheses. The resource also includes a supplementary resource — Novel FDA Drug Approvals — that features new molecules approved by the FDA by year. NCATS will update the portal regularly to ensure the broader research community has access to the most comprehensive and accurate information available. And novel algorithms developed at NCATS will enable data to be automatically aggregated in the portal. I anticipate that NCATS Inxight: Drugs will help investigators obtain the data they need to more effectively advance drug development and repurposing efforts that address unmet medical needs. That, in turn, will help NCATS — and the entire biomedical research community — reach our goal of getting more treatments to more patients more quickly. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences Dec. 6, 2018: Team Science Champions! At NCATS, we often say that translation is a team sport. I use this aphorism because it helps convey how team science is more than just collaborating with other researchers: It is working as an integrated and interdependent group to accomplish a common goal that cannot be achieved alone or with a single type of expertise. Team science promises to drive major improvements in translational efficiency and effectiveness, since what is difficult or impossible for one member of the team may be easy for a teammate with a different skill set. In fact, we have found that the more intractable the problem, the more diversity in team expertise is needed to solve it. But as in all areas of science, team science requires data (e.g., on what kinds of teams work best to solve particular kinds of problems, and how those teams should be constructed, led, incentivized, and evaluated). Two major events have recently advanced this aspect of translational science. The first is evidence published by the NCATS Biomedical Data Translator program in the November 2018 issue of Clinical and Translational Science. Recall that the scientific goal for Translator is ambitious: Develop a tool that seamlessly integrates multiple types of existing data sources to help researchers identify connections among disparate data. Toward this end, NCATS designed a correspondingly unique approach: In the two years since the program launched, our Center has assembled 11 teams from 26 institutions that had to quickly begin working together — and trusting each other — to make progress. Most of the Translator team members did not know each other previously, nor had these experts in their fields ever worked so closely on a project like this before. Challenges included the hurdles of divergent scientific languages, cultures, and practices; multi-institution coordination; and the critical importance of trust, which was fostered by NCATS’ encouragement of open discussion and constant feedback. The first of the articles published this month by the Translator describes the amazing scientific progress made in the first two years of the program. The second article is devoted to the unique culture, structure, and ethos the team developed that powered their scientific progress. The Translator investigators attribute their success to diverse skill sets, skillful management, and a “communitarian spirit,” which allowed them to exceed their own expectations in tackling the complex issues presented by the Translator mission. The second big event in team science was our Clinical and Translational Science Awards (CTSA) Program’s Great CTSA Team Science Contest, which showcased collaborations across the consortium. Despite the contest’s prizes not including money — just bragging rights and a T-shirt — the CTSA Program hubs outdid everyone’s expectations, with 170 submissions from more than 40 institutions showcasing a range of team science innovations. The 11 winners presented posters and received their well-earned rewards at the October 2018 CTSA Program investigator meeting. One of the contest’s winning projects, which paired clinicians with engineering students to address pressing medical challenges, included a team that developed a smartphone app to help emergency department staff coordinate care for trauma patients with staff from the operating room, imaging, anesthesiology and intensive care. In pilot tests, the app improved teamwork scores and reduced the amount of time patients spent in the emergency room. The contest organizers are now looking at how these creative ways to conduct team science can be disseminated across the CTSA Program. These two exciting developments not only show the enormous potential of translation as a team sport, but also establish new paradigms that can be implemented broadly to improve the efficiency of the translational process for all diseases. Christopher P. Austin, M.D. Director National Center for Advancing Translational Sciences | 2018 Director’s Messages | 2018 Director’s Messages | ||||||
| 8831 | Other CTSA Program Activities | Diversity Supplements Through research supplements to promote diversity in health-related research, the CTSA Program supports the enhancement of the diversity of the research workforce by recruiting and supporting students, postdoctorates and eligible investigators from groups that have been shown to be underrepresented in health-related research. Learn more about the Diversity Supplements. | Other CTSA Program Activities | Other CTSA Program Activities | ||||||
| 8830 | CTSA Program Projects & Initiatives | Current CTSA Program Projects & InitiativesStreamlined, Multisite, Accelerated Resources for Trials Institutional Review Board To streamline the institutional review board (IRB) process for multisite clinical research, we support the development of the Streamlined, Multisite, Accelerated Resources for Trials (SMART) IRB Platform. SMART IRB is a single IRB reliance platform for multisite clinical studies, enabling study sites to rely on a single IRB of record. Learn more about the SMART IRB.Trial Innovation NetworkThe Trial Innovation Network is a new collaborative initiative composed of three key organizational partners: three Trial Innovation Centers, a Recruitment Innovation Center and the CTSA Program hubs. Our vision for the Trial Innovation Network is to address critical roadblocks in clinical trials and to accelerate the translation of novel interventions into life-saving therapies. Learn more about the Trial Innovation Network.CTSA Program Collaboration Innovation AwardsCTSA Program Collaborative Innovation Awards (CCIA) are intended to foster research collaboration by encouraging teams from three or more CTSA Program hubs to work together to develop, demonstrate and disseminate innovative, experimental approaches to overcoming translational science roadblocks. Learn more about the CTSA Program CCIA.CTSA Program Rural Health EffortsRural Americans, who make up about one-fifth of the U.S. population, face numerous health challenges including higher rates of poverty, fewer healthcare specialists, high rates of risk behaviors, and remote locations that make it difficult to access care. Due to the CTSA Program’s nationwide reach and ability to foster diverse collaborations and engage communities, funded investigators are uniquely positioned to support interventions that improve health in rural America. Learn more about these efforts.Community Engagement Across the CTSA Program ConsortiumCTSA Program hubs are working hand in hand with community partners to build strong relationships, understand community needs and improve community health. This commitment to community engagement accelerates clinical research, expands treatment delivery and speeds the response to public health challenges. Learn more about the community engagement efforts.Evolve to Next-Gen ACT (ENACT) NetworkThe Evolve to Next-gen ACT health informatics platform builds upon prior work of the CTSA enabling investigators and trainees at CTSA hubs to conduct electronic health record (EHR)–based research on any disease or condition across the network. The next generation of this platform will offer enhanced data quality metrics and ontologies, modern analytic capabilities (such as natural language processing and artificial intelligence/machine learning), provide more interoperability with common data models (such as OMOP, PCORnet, i2b2), and support both federated and secure temporary centralized data enclaves for more meaningful EHR-based research. Learn more about the Evolve to Next-gen ACT platform.CTSA Program Coordinating CenterThe Coordination, Communication, and Operations Support (CCOS) Center serves as the coordinating center for the CTSA Program. The primary goal is to facilitate the work of collaborative scientific teams within the program, while also providing logistical support and ensuring a smooth flow of data, information, and insights throughout the network. Learn more about CCOS.Past InitiativesCommon Metrics Initiative The Common Metrics Initiative is designed to assess and optimize the CTSA Program’s overall impact on the nation’s health. Establishing a set of standard evaluation measures across CTSA Program hubs helps focus program activities, streamline data collection, and demonstrate measurable progress toward program goals, including improvements in research translation and workforce development. Learn more about the Common Metrics Initiative.National Center for Data to HealthThrough the National Center for Data to Health (CD2H), informatics experts are using CTSA Program resources to develop standardized approaches and best practices that address operational and institutional barriers to sharing data. The CD2H aims to help make data more meaningful, open and accessible, a key goal in NCATS’ efforts to improve translational science. Learn more about the CD2H. | /sites/default/files/yale_opioid_900x600.jpg | CTSA Program Projects & Initiatives | /sites/default/files/yale_opioid_900x600.jpg | CTSA Program Projects & Initiatives | ||||
| 8814 | Funded Activities Under the CTSA Program | Download the table (PDF - 121KB) td, th { max-width: 140px; word-wrap: break-word; } NCATS Clinical and Translational Science Awards Program1 Fiscal Year 2014 Actual Fiscal Year 2015 Actual Fiscal Year 2016 Actual Fiscal Year 2017 Actual Fiscal Year 2018 Actual CTSA Program Hubs2 Number of Hub awards3 58 58 57 57 58 Hub Awards (A UL1 award with a linked KL2 award and an optional TL1 award)4 $404,954,499 $441,922,552 $449,584,228 $447,800,122 $459,342,839 Administrative Supplements to Hub Awards5 $44,204,713 $18,534,775 $9,851,866 $6,367,377 $21,790,276 Bridge Awards (U54) $16,798,746 $3,528,613 $3,560,718 $3,497,558 $0 CTSA Program Collaboration Initiatives — all awards to CTSA institutions CTSA Program Collaborative Innovation Awards (U01/R21) $8,602,736 $14,402,042 $24,130,055 Consortium Centers (U24/U54) RIC/TIC/CD2H/Coordination $2,420,706 $2,741,255 $16,354,755 $29,878,310 $22,037,558 Subtotal of Funding to CTSA Program Institutions $468,378,664 $466,727,195 $487,954,303 $501,945,409 $527,300,728 Other CTSA Program Activities6 Other (K23/R13/U13/U19/T15/U2C/U24) $1,402,448 $1,277,800 $265,000 $600,000 $643,697 Loan Repayment Program $2,006,148 $1,986,781 $2,001,190 $2,009,444 $2,508,139 Program Management (includes NIH and DHHS assessments and transfers) $5,432,517 $7,399,063 $9,779,507 $11,569,957 $12,326,808 Grand Total $477,219,777 $477,390,839 $500,000,000 $516,124,810 $542,779,372 Notes: To view a list of awards from NIH RePORTER, please click on underlined dollar amounts. RePORTER provides the most up-to-date information available on funded projects, so the data are not frozen and changes in the administrative details of prior awards can occur. 1 NCATS received CTSA Program-specific appropriations language beginning in FY2014. CTSA Program-specific appropriations language in FY2012 and FY2013 was directed to the NIH Office of the Director. 2 A CTSA Program Hub is defined as a UL1 award with a linked KL2 award and an optional TL1 award. No Cost Extensions (NCE) to Hub awards do not receive funding from NCATS in a particular fiscal year. NCEs do not count as funded Hubs in that fiscal year and are therefore not reflected in the table. 3 In FY2014, NCATS did not issue a CTSA Program Hub funding announcement as the program was being re-structured in response to the 2013 IOM recommendations. Eight CTSA Program Hubs that were positioned to re-compete for Hub awards in FY2014 were issued orderly close-out supplements to enable them to remain active until a FY2015 funding announcement was available and posted. 4 The totals reported in this table reflect only NCATS' investment in the CTSA Program. For FY2017, NIH RePORTER data shows an additional $407,214 due to co-funding provided by DHHS. 5 NCATS investment in Administrative Supplements for FY2014 was $93,000 less than what is shown in NIH RePORTER. NCATS investment in Administrative Supplements for FY2016 was $23,389 more than what is shown in NIH RePORTER. Grand total amounts for the fiscal years are accurate. 6 For a glossary of NIH award codes, visit https://grants.nih.gov/grants/funding/funding_program.htm. | Funded Activities Under the CTSA Program | Funded Activities Under the CTSA Program | ||||||
| 8771 | NCATS-Supported Researchers Demonstrate Value in Community-Based Research Consultation Service | Translational Science Highlight A community-based research evaluation model of consultation services is helping to translate clinical practice observations into research-supported treatment approaches. For many clinicians, it can be difficult to gather the research data needed to determine how effective a treatment will be for a patient. Ensuring that observations from clinical practice can lead to better therapies is a translational science priority that NCATS seeks to support through its Clinical and Translational Science Awards (CTSA) Program. Licensed massage therapist (LMT) Diane Mastnardo has demonstrated how challenging this effort in translation can be. She was certain that massage therapy helped her clients by relieving pain, increasing joint flexibility, improving balance and posture and speeding recovery from injuries. Yet medical providers — citing a lack of scientific evidence demonstrating health benefits of massage — often were reluctant to refer their patients to LMTs for therapy. Mastnardo had hit a translational barrier: She needed data about massage therapy, but she couldn’t collect the information without research training or access to resources to carry out a study that could generate the data. Mastnardo’s situation wasn’t unique. Many community members want to play an active role in research, even undertaking studies themselves. At the same time, investigators supported through the CTSA Program value the role of community participation as they design and conduct studies. They often seek out opportunities to collaborate with community members, patients and clinicians to help guide research that can lead to new treatments to improve health. These mutual needs and the resulting partnerships are the foundation of community-based research (CBR), which differs from traditional biomedical research approaches. Rather than focusing research on the community, CBR is carried out with the community. “CTSA Program-supported investigators have implemented a broad range of CBR initiatives to encourage dialogue about health concerns and clinical research,” said Pamela McInnes, D.D.S., M.Sc.(Dent.), NCATS deputy director and the Center’s acting director of the Division of Clinical Innovation. “They often partner with organizations to learn about local health needs, foster mutual trust and provide information about and access to clinical trials.” Evaluating the Consultation Services’ Impact on CBR Since 2004, the Center for Reducing Health Disparities of the Clinical & Translational Science Collaborative (CTSC) of Cleveland, based at Case Western Reserve University, has provided a consultation service for academic and community researchers to help them with CBR projects. The consultation team is a multidisciplinary group of experts with diverse academic, medical, research and cultural backgrounds. The consultants help anyone with an interest in CBR, including biomedical researchers, students and trainees but also entities beyond traditional academic research, such as community organizations, health care providers and individuals who, like Mastnardo, want to conduct a study. The CTSC CBR consultation team meets weekly to assist researchers, clinicians and community members with their research projects. (Clockwise starting from left: Maria Figueroa; J. Daryl Thornton, M.D., M.P.H.; Ashwini Sehgal, M.D.; Katrice Cain, M.A.; Jacqueline Dolata, M.B.A.; Anne Huml, M.D.; Karen Scott, M.P.A. Not pictured: Cathy Sullivan, M.S., RD, LD, and Earl Pike.) Over the years, the CTSC consulting team has advised clients on a wide array of research-related challenges, including research project design, survey development, regulatory matters, recruitment strategies, translation services and focus group design. The CTSC recently evaluated the effectiveness of these consultation services and reported the results in the Journal of Clinical and Translational Science. Evaluating the impact of consultation services on community engagement and CBR is challenging. “Tracking parameters such as numbers of clients and types of assistance provided is pretty straightforward,” said Clara Pelfrey, Ph.D., director of evaluation for the CTSC. “Discerning trends and obtaining long-term data on the outcomes of research projects is more difficult.” Those are key reasons why few, if any, such evaluations have been reported — until now. Pelfrey spoke with consultation service staff in 2014 about capturing data on CBR activities and developing a process to evaluate the service’s effectiveness. First, Pelfrey and the CBR consultants delineated the steps involved in consultation and project completion, resulting in a Stages of Engagement framework. Next, more than 10 years of data were imported into REDCap, a CTSA Program-supported application that helps users capture data, generate reports and detect trends. The evaluation team then developed several survey instruments and interviewed some former clients to fill information gaps and learn about the outcomes of research projects. Clients from five universities and three hospitals, as well as 14 community members or organizations, requested consultations between January 2011 and July 2015. These clients benefited from the expert knowledge, community connections and project guidance provided by the consultation service team, increasing the likelihood of study completion and achievement of research goals. The Making of a Citizen-Scientist Mastnardo’s first encounter with the CBR team happened at a community event that brought together local people and CTSC researchers to foster CBR. There she met Katrice Cain, M.A., program development manager for the Center for Reducing Health Disparities, which is supported through the CTSC Community Research Partnership Core. “Diane was interested in learning about incorporating research into her massage practice to collect evidence for medical professionals and insurers to give their patients access to therapeutic massage services,” Cain said. Cain connected Mastnardo to the CBR consultation service and introduced her to Ashwini Sehgal, M.D., co-director of CTSC’s Community Research Partnership Core and a nephrologist with the MetroHealth System, where he treats patients whose kidneys have failed. Sehgal wanted to find a way to alleviate muscle cramps experienced by many patients undergoing dialysis. Unfortunately, when cramps occur, dialysis must stop, depriving patients of the procedure’s full therapeutic benefit. Sehgal wondered whether massage therapy could relieve the cramps, allowing dialysis to proceed. Diane Mastnardo (left), founder and director of MNOPBRN, and Jeanmarie Mullner Rose, M.P.A. (right), presented a poster at a 2015 scientific meeting about the launch of the network established to research the effectiveness of massage therapy. Sehgal suggested a collaborative pilot study with Mastnardo and other LMTs to see whether massage might help relieve the muscle cramping associated with dialysis. The CBR consultation service helped Mastnardo make the leap from LMT to clinical researcher. “Through the CBR consultation service, I was able to access research training; learn about study design, regulations and bioethics; and receive grant-writing assistance,” Mastnardo said. “I also was inspired to set up the Massage Northern Ohio Practice-Based Research Network (MNOPBRN), which now has 90 registered LMT members.” With the support of the core and the consultation service, Mastnardo and her colleagues developed a pilot study and received a grant through CTSC’s Practice-Based Research Network. “The CBR consultation service helped us frame the research question, develop a stepwise approach to creating a research plan, set up study sites and prepare for protocol review by the institutional review board,” Mastnardo explained. MNOPBRN partnered with community dialysis centers to conduct a small randomized controlled trial. Research participants who received massages reported fewer cramping episodes during and between dialysis sessions. The results were presented at professional meetings and published in the International Journal of Therapeutic Massage & Bodywork. In November 2017, at the North American Primary Care Research Group conference in Montreal, Mastnardo presented a poster on perceptions of and barriers to massage therapy. “To build on our momentum, we hope to identify funding sources and collaborators for larger studies on the health outcomes massage therapy affects: pain, stress and anxiety,” she said. Mastnardo credits her research success to the CBR consultation service and CTSC’s support. “The consult service provides a wealth of resources and expertise,” she said. “Whenever I hit an impasse, the consultants came up with solutions.” “Her story demonstrates how community members can become productive researchers,” Pelfrey added. “In fact, she is now a contributing member on the CBR consultation service and brings a fresh viewpoint as a true citizen-scientist.” Posted December 2017 | CTSA Program-supported researchers developed a community-based research (CBR) evaluation model to gauge how consultation services help translate clinical observations into treatments. | /sites/default/files/case-western-poster_900x600.jpg | NCATS-Supported Researchers Show Value of CBR Consultation Service | CTSA Program-supported researchers developed a community-based research (CBR) evaluation model to gauge how consultation services help translate clinical observations into treatments. | /sites/default/files/case-western-poster_900x600.jpg | NCATS-Supported Researchers Show Value of CBR Consultation Service | ||
| 8706 | Gene Therapy Platform for Rare Diseases | Genetic Therapies for Rare Diseases There are approximately 10,000 identified rare diseases, yet only a few hundred have treatments are approved. Gene therapy is particularly relevant to rare disease patients, as more than 80 percent of rare diseases have a known monogenic (single-gene) cause. Traditional small molecule drugs often work by minimizing symptoms rather than curing the disease. When treating a chronic condition, this can mean frequent administration of the drug or drugs required to manage the condition. In contrast, gene therapy has the potential to correct underlying genetic defects, offering a cure rather than simply managing symptoms. Moreover, successful gene therapy may require only a single dose to confer lifelong improvement rather than requiring a lifetime of ongoing treatment. Developing a Gene Therapy "Toolbox" Scientists have been researching gene therapies for decades, but the U.S. Food and Drug Administration only recently approved the first gene therapy for patients in 2017. As a new modality of treatment, gene therapy presents unique technical and regulatory challenges. To help accelerate the field of gene therapy, the TRND program has initiated a suite of pilot projects in collaboration with biotechnology and academic groups. Projects are designed to address specific obstacles in gene therapy development. New technologies to scale up gene-vector manufacturing and to deliver the transgene to the right tissue at the right time and dosage are being developed. TRND’s goals are to develop these technologies and disseminate the best practices to achieve regulatory approval for new gene therapies. By building a toolbox of technologies and information, TRND aims to improve the speed of development and reduce costs for gene therapy in general. Technologies Under Development Manufacturing Plug-and-play manufacturing processes for AAV (adeno-associated virus) serotypes Compendium of standard analytical and bioanalytical methods Cell suspension technology Cell potentiation technology Delivery Devices to deliver therapeutic vector to the CNS (central nervous system) Platform vectors to deliver groups of transgenes to targeted tissues Projects In Platform Therapeutic Area Vector Technology Collaborator AADC Deficiency AAV-2 Agilis Biotherapeutics Pompe Disease AAV-2/8 Duke University Duchenne Muscular Dystrophy AAV-9 Solid Biosciences; University of Missouri Publications Brook PJ, Yang NN, Austin CP. Gene therapy: the view from NCATS. Hum Gene Ther. 2016 Jan;27(1):7–13. Kodippili K, Hakim CH, Pan X, Yang HT, Yue Y, Zhang Y, et al. Dual AAV gene therapy for Duchenne muscular dystrophy with a 7-kb mini-dystrophin gene in the canine model. Hum Gene Ther. 2017 Aug 4. doi: 10.1089/hum.2017.095. Nance ME, Hakim CH, Yang NN, Duan D. Nanotherapy for Duchenne muscular dystrophy. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017 Apr 11. doi: 10.1002/wnan.1472. Han SO, Ronzitti G, Arnson B, Leborgne C, Li S, Mingozzi F, Koeberl D. Low-dose liver-targeted gene therapy for Pompe disease enhances therapeutic efficacy of ERT via immune tolerance induction. Mol Ther Methods Clin Dev. 2017 Jan 11;4:126–36. doi: 10.1016/j.omtm.2016.12.010. Hwu WL, Muramatsu S, Tseng SH, Tzen KY, Lee NC, Chien YH, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012 May 16;4(134):134ra61. doi: 10.1126/scitranslmed.3003640. Related Information News Release: Gene Therapy for Rare, Pediatric Condition Moves Closer to Reaching U.S. Patients Web Feature: NCATS’ Preclinical Collaboration Enables Gene Therapy for Rare Muscle Disease to Advance to Clinical Trial | Gene Therapy Platform for Rare Diseases | Gene Therapy Platform for Rare Diseases | ||||||
| 8705 | Drug Repurposing Screening for Rare and Neglected Diseases | Why Examine Existing Compounds? There are approximately 7,000 rare and neglected diseases that currently lack effective treatments. Drug discovery and development can take more than a decade and billions of dollars to deliver new treatments to patients. Due to the high costs and long timelines, rare and neglected diseases are largely ignored by the pharmaceutical industry. Finding new uses for existing compounds that already have cleared several key steps along the development path, an approach known as drug repurposing, is a more rapid way to identify potential treatments for these conditions. Testing Compounds and New Technologies The Division of Preclinical Innovation has established the NCATS Pharmaceutical Collection, a library of 2,500 approved drugs and 1,000 investigational compounds that have been approved for human clinical testing. These compounds have accumulated preclinical and clinical data that could aid the process of further drug development. Our goal is to accelerate the development of new treatments for rare and neglected diseases by screening these compounds for new therapeutic purposes. We apply new technologies and approaches for screening, such as phenotypic cell-based disease models with patient-derived induced pluripotent cells (iPSCs) and high-content screening platforms. Program Goals The TRND Repurposing Screening Group collaborates with leading investigators at NIH, universities and other nonprofit research institutions, and private-sector companies. Our objectives include (1) identification of drug targets or disease phenotypes for assay development, (2) assay development and optimization for high-throughput screening, (3) drug repurposing screening to identify active compounds that reduce disease phenotypes, (4) confirmation of compound activity by using in vitro assays and animal models, and (5) advancement of the newly identified compounds to clinical trials for the treatment of rare and neglected diseases. Research Activities The TRND Repurposing Screening group has engaged in diverse collaborations in a range of scientific areas. Recent examples include the following: Drug-resistant bacterial infections Sun W, Weingarten RA, Xu M, Southall N, Dai S, Shinn P, et al. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria. Emerg Microbes Infect. 2016 Nov 9;5(11):e116. Ebola and Zika virus infection Sun W, He S, Martínez-Romero C, Kouznetsova J, Tawa G, Xu M, et al. Synergistic drug combination effectively blocks Ebola virus infection. Antiviral Res. 2017 Jan;137:165–72. Epub 2016 Nov 24. pii: S0166-3542(16)30616-7. Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016 Oct;22(10):1101–7. iPSC disease models Long Y, Xu M, Li R, Dai S, Beers J, Chen G, et al. Induced pluripotent stem cells for disease modeling and evaluation of therapeutics for Niemann–Pick disease type A. Stem Cells Transl Med. 2016 Dec;5(12):1644–55. Xu M, Motabar O, Ferrer M, Marugan JJ, Zheng W, Ottinger EA. Disease models for the development of therapies for lysosomal storage diseases. Ann N Y Acad Sci. 2016 May;1371(1):15–29. Kaewkhaw R, Swaroop M, Homma K, Nakamura J, Brooks M, Kaya KD, et al. Treatment paradigms for retinal and macular diseases using 3-D retina cultures derived from human reporter pluripotent stem cell lines. Invest Ophthalmol Vis Sci. 2016 Apr;57(5):ORSFl1–11. Beers J, Linask KL, Chen JA, Siniscalchi LI, Lin Y, Zheng W, et al. A cost-effective and efficient reprogramming platform for large-scale production of integration-free human induced pluripotent stem cells in chemically defined culture. Sci Rep. 2015 Jun;5:11319. | Drug Repurposing Screening for Rare and Neglected Diseases | Drug Repurposing Screening for Rare and Neglected Diseases | ||||||
| 8671 | Drug Discovery, Development and Deployment Maps | The Drug Discovery, Development and Deployment Maps (4DM) provide dynamic representations of the modern therapeutic development process to more easily identify inefficiencies and integrate efforts to expedite new therapies for patients. The maps provide a common framework for discussing the therapeutic development process and serve as an education tool for those who are new to it. A common language and collective knowledge base for therapeutic development is essential to enable systemwide improvements that will benefit patients. The 4DM can help facilitate dialogue among those interested or participating in drug development to explore innovative solutions to existing bottlenecks and potential collaborative action to overcome those barriers and accelerate new medicine discovery. An expanded, interactive version of the 4DM provides a more dynamic map interface for enhanced usability and an interactive experience compared with the static version below. Users can zoom into and out of areas of the process to view different levels of complexity, find information and best practices, and connect to relevant NCATS programs and resources. Two versions of the 4DM are available below: one for small molecules (Figure A), and another for biologics, using monoclonal antibodies as the representative therapeutic (Figure B). Small molecule drugs are chemically manufactured compounds of relatively low molecular size that make up the vast majority of drugs on the market today. Biologic drugs are large complex molecules manufactured by a living system, such as a microorganism, or plant or animal cells, and include antibodies and vaccines. These two maps illustrate some of the unique differences between the development of biological drugs and that of more traditional small molecule therapeutics. Both files are licensed to the public under the Creative Commons Attribution-Share Alike International 4.0 (CC BY-SA 4.0) license, which allows use and adaption as long as the user provides attribution and shares any adaptations back to the public under the same license. The 4DM were developed by members of an Action Collaborative of the Forum on Drug Discovery, Development, and Translation (the Forum) of the National Academies of Sciences, Engineering, and Medicine. The Forum includes leaders from private sector sponsors of biomedical and clinical research; federal agencies sponsoring and regulating biomedical and clinical research; foundations; the academic community; consumers; and federal and private health plans. More detailed information regarding the 4DM and its development was published on December 22, 2017 in both Nature Reviews Drug Discovery and Clinical and Translational Science. Figure A. 4DM Small Molecule Map. Map depicting the interconnected nature of key steps in the drug development lifecycle for small molecules. The steps are grouped into eight identified neighborhoods, each depicting the steps and processes necessary to advance within a particular stage of development. Steps within each individual neighborhood are frequently dependent upon both other steps within that neighborhood as well as with steps in other neighborhoods, resulting in a complex and nonlinear development process. This file is licensed to the public under the Creative Commons Attribution-Share Alike 4.0 license, which allows use and adaption as long as the user provides attribution and shares any adaptations back to the public under the same license. The figure should be attributed to: Wagner JA, Dahlem AM, Hudson LD, Terry SF, Altman RB, Gilliland CT, DeFeo C, and Austin CP. Drug Discovery, Development and Deployment Map (4DM): Small Molecules. Available at https://ncats.nih.gov/translation/maps. Last updated November 2017. Download this map here. Figure B. 4DM Biologics Map. Map depicting the interconnected nature of key steps in the drug development lifecycle for biologics. The steps are grouped into eight identified neighborhoods, each depicting the steps and processes necessary to advance within a particular stage of development. Steps within each individual neighborhood are frequently dependent upon both other steps within that neighborhood as well as with steps in other neighborhoods, resulting in a complex and nonlinear development process. The figure should be attributed to: Wagner JA, Dahlem AM, Hudson LD, Terry SF, Altman RB, Gilliland CT, DeFeo C, and Austin CP. Drug Discovery, Development and Deployment Map (4DM): Biologics. Available at https://ncats.nih.gov/translation/maps. Last updated November 2017. Download this map here. | /sites/default/files/Figure%20A%20-%204DM%20Small%20Molecules%20Map.jpg | Drug Discovery, Development and Deployment Maps | /sites/default/files/Figure%20A%20-%204DM%20Small%20Molecules%20Map.jpg | Drug Discovery, Development and Deployment Maps |
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