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| 594 | TRND Research Leads to NIH Trial to Test Drug for Niemann-Pick Type C1 | Niemann-Pick disease type C1 is a rare, inherited disease characterized by progressive impairment of motor and intellectual functions in early childhood. Life expectancy often does not exceed an individual’s teenage years. To date, the disease is incurable, and no drugs approved by the Food and Drug Administration are available to treat it. In 2009, the NIH Therapeutics for Rare and Neglected Diseases (TRND) program, which is led now by NCATS, chose to repurpose chemical substance called cyclodextrin, normally used as an inactive ingredient in certain formulated drug products, as a potential therapeutic for Niemann-Pick type C1. Today, a promising new treatment is on the horizon. On Jan. 23, 2013, NIH initiated a Phase I clinical trial to evaluate the safety and effectiveness of cyclodextrin as a potential therapy for Niemann-Pick type C1. This progress is the result of the collaborative efforts of an award-winning, multidisciplinary team of experts from NCATS, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke (NINDS), and the National Human Genome Research Institute; Janssen Research & Development, LLC; Washington University in St. Louis School of Medicine; Albert Einstein School of Medicine, New York City; and University of Pennsylvania, Philadelphia. A number of family support groups have made significant contributions that have led to the launch of the clinical trial through the funding of Niemann-Pick research and patient support. They include the Ara Parshegian Medical Research Foundation, the International Niemann Pick Disease Alliance, the National Niemann Pick Disease Foundation, and Support of Accelerated Research for Niemann-Pick type C. In addition, the Office of Rare Disease Research, prior to joining NCATS, provided early support for the work through an NIH Bedside-to-Bench award to Forbes Porter, M.D., Ph.D., the trial's senior investigator and NICHD clinical director. Members of the collaborative Niemann-Pick type C1 project team. (NCATS Photo/Lisa Goodman) Why does cyclodextrin look so promising? Excessive amounts of cholesterol accumulate within the cells of the liver, spleen and brain of patients with Niemann-Pick type C1. Animal studies conducted by several academic researchers, including TRND collaborators, Steve Walkley, D.V.M., Ph.D., of the Albert Einstein College of Medicine, and Charles Vite, D.V.M., Ph.D., at the University of Pennsylvania, suggested that cyclodextrin can reduce cholesterol storage in cells and improve neuropathology and liver function. Given this evidence, TRND supported studies to evaluate the drug's safety in animals. The program also enabled the development of a test measuring blood levels of a biomarker that increases as a result of cyclodextrin treatment in the laboratory of Daniel Ory, M.D., at Washington University in St. Louis. The clinical trial researchers will use the test to track the drug's effects in participants. "Initiation of this clinical trial is the culmination of two decades of basic and clinical research to understand and develop therapies for Niemann-Pick type C1," Porter said. "The efforts of the collaborators who make up the TRND team on this project have greatly accelerated translating cyclodextrin from the laboratory to the clinic." The trial will test multiple doses of cyclodextrin in nine patients to determine a safe dose that will support an expanded Phase II trial to begin to evaluate the effectiveness of the drug. The trial's researchers are in the early stages of collaborating with the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), which is administered by NINDS, to plan a larger, multicenter Phase II trial of cyclodextrin. During the initial screen that identified cyclodextrin activity in Niemann-Pick type C1 cells, NCATS researchers from the Division of Preclinical Innovation also identified a second potential lead for further study: delta-tocopherol, a form of vitamin E. Early preclinical work has produced promising results. According to John McKew, Ph.D., acting director of the NCATS Division of Preclinical Innovation, chief of its Therapeutic Development Branch, and director of TRND, "The multidisciplinary nature of this Niemann-Pick collaboration establishes a generalizable model that can be used in the pursuit of treatment candidates for rare and neglected diseases." Posted February 2013 | ||||||||
| 593 | Tox21 Researchers Analyze Potential Negative Effects on Human Health of Thousands of Chemicals | Throughout our lives, we may be exposed to thousands of chemicals in our food, household cleaning products, medicines and environment. However, scientists know little about the potential for most of these substances to be hazardous to human health (i.e., their toxicity). Traditional toxicity testing often involves animals, which can be a slow and costly approach that often does not predict accurately how humans will respond to a chemical. To address these challenges, researchers from the Toxicology in the 21st Century (Tox21) consortium have developed faster, cheaper and more effective toxicity testing methods. Tox21 is a collaboration among researchers from NIH’s NCATS and the National Institute of Environmental Health Sciences (NIEHS), the Environmental Protection Agency (EPA), and the Food and Drug Administration (FDA). Tox21 scientists use a robotic system located in NCATS’ Rockville, Maryland, laboratories to perform automated tests (called assays) that expose cells and proteins to thousands of chemicals. Tox21 scientists currently are working on the second phase of the effort to screen a library of more than 10,000 chemicals (Tox21 10K) — the largest analysis of its kind. The library consists of substances to which people are regularly exposed. These include pesticides, industrial chemicals, food additives and drugs. The effort already has generated nearly 50 million data points that will provide information about the potential effects of the chemicals on human biological functions. Tox21 scientists published the first results from screening the Tox21 10K library in the July 11, 2014, issue of Scientific Reports. The group developed an assay to test the effects of the approximately 10,000 chemicals on estrogen receptors, which are activated by the estrogen hormone and convey signals to the body that regulate reproductive functioning. Some chemicals may cause certain cancers or birth defects by mimicking estrogen and activating its receptors. For example, bisphenol A (BPA), an industrial chemical used to make plastics and found in water bottles, has been linked to birth defects in infants. Animal studies suggest that BPA could cause these effects by mimicking estrogen. Many other compounds in food and the environment similarly may affect the estrogen receptor by turning it on or off and pose health hazards; therefore, performing the chemical screen with the estrogen receptor assay was a high priority for the Tox21 group. The screens reported in the paper identified chemical classes that were known to interact with estrogen receptors, as well as some not previously known to scientists. Enter the NCATS Robots The screen’s unprecedented scale was not its only distinguishing feature. The NCATS robotic system was developed to perform a technique called quantitative high-throughput screening. This innovative method enables the team to run each compound through the screen three times at 15 different concentrations. This approach is a key feature of the NCATS’ screening programs, and “it gives us higher confidence in the data and assures us that any given result is not just a trend, but real biological activity of a molecule,” explained Anton Simeonov, Ph.D., acting deputy director of the NCATS Division of Preclinical Innovation and an author on the paper. Additionally, the assays included two versions of the estrogen receptor, one partial and one full length. The partial version of the receptor contains the ligand binding domain (LBD), which is the region that attaches to compounds, including the estrogen ligand. The full-length version of the receptor better mimics the biological environment, but chemicals could interact with it in areas other than the LBD, producing a different response than would be expected from estrogen and similar compounds. Screening the chemicals against both versions of the receptor allowed the team to compare the results to get a more accurate idea of which compounds truly affect the receptor by interacting with it like estrogen. “This study’s scale and comprehensive nature, with its exhaustive testing of compound activities in two different receptor versions, make it unique. It is the first of its kind to test so many chemicals against the estrogen receptor, which is an important focus of toxicology,” Simeonov said. An Effective Federal Collaboration The successful completion and publication of the estrogen receptor screen shows the ability of several federal agencies to pool resources and provide complementary expertise to carry out a large-scale project. “This collaboration is probably one of the best-coordinated events in toxicology and human health assessment,” said Robert Kavlock, Ph.D., director of the National Center for Computational Toxicity at the EPA and an author on the paper. “It is a seamless organization — it’s often hard to tell who works for what agency.” Raymond Tice, Ph.D., chief of the National Toxicology Program at NIEHS and another of the paper’s authors, added, “This project is something the government is uniquely capable of doing, and this initial publication of the estrogen receptor data demonstrates the success of this federal collaborative model.” The Tox21 group submitted the data reported on in the paper to the National Library of Medicine’s PubChem website, making it available for the public and other scientists to freely access. The results will enable the Tox21 team — as well as other scientists — to prioritize chemicals for further in-depth studies to define their effects on human health. In releasing the data publicly, the Tox21 group plans to harness the power of crowdsourcing to challenge the general scientific community to develop innovative and original ways to analyze the data. “The data provide scientists with the initial roadmap that will enable them to interpret the results and predict the chemicals’ effects on human biology,” Simeonov said. In the near future, Tox21 experts plan to publish similar data sets from screens of the Tox21 10K library in assays of stress response pathways, which are designed to identify compounds that can damage or kill cells. The team will continue to test the chemical library and release screening data, moving Tox21 closer to its goal of transforming toxicity testing into a cheaper, more efficient, and more effective enterprise, bringing about the ultimate endpoint of improved human health. In addition, NCATS recently launched the Tox21 Data Challenge 2014, which is a crowdsourcing competition to develop predictive models for chemical toxicity from data generated from 12 Tox21 assays, including the estrogen receptors and stress response pathways information. This public sharing of Tox21 data and methods reflects the NCATS mission to disseminate knowledge and information to arm scientists with tools to carry out more efficient and transformative translational research. Posted August 2014 | ||||||||
| 592 | Tissue Chip Projects Highlighted in Major Journal | Researchers from NIH, the Food and Drug Administration and the Defense Advanced Research Projects Agency collaborate to improve the process for predicting whether new drugs will be safe or toxic in people. Current ways of predicting toxicity include testing a potential drug in animals, such as mice and rats. This procedure is expensive and often unreliable in that it doesn’t always predict what happens in people. Through the Tissue Chip for Drug Screening program at NCATS, researchers are developing 3-D human tissue chips. These human microphysiological systems — “organs on a chip” — are miniature platforms intended to model accurately the structure and function of the 10 human organ systems, such as the respiratory system, circulatory system and nervous system. Once these miniaturized models are developed, researchers can use them to test a potential drug, vaccine or biologic agent for toxic effects. Because these chips will be working models of human systems, investigators can use them to determine whether a substance is likely to be safe or toxic in people in a faster, more cost-effective manner than current methods. On Dec. 20, 2013, the journal Stem Cell Research & Therapy published a supplement that provides an overview of the Tissue Chip projects. Stem Cells on Bioengineered Microphysiological Platforms for Disease Modeling and Drug Testing features reviews of the progress NCATS grantees have made to date on innovative cell resources and model systems. Following a brief introduction authored in part by NCATS’ Danilo Tagle, Ph.D., who oversees the Tissue Chip program, 18 projects are highlighted. Introduction The National Institutes of Health Microphysiological Systems Program Focuses on a Critical Challenge in the Drug Discovery Pipeline Currently, only 18 percent of new therapeutic compounds ever reach phase II human trials. Of those that pass that test, only half are successful in phase III trials, which means enormous effort and resources are spent on drug candidates that ultimately fail. One of the most common reasons for these late failures is unanticipated toxicity based on previous preclinical data. Use of organ systems on a chip developed through this initiative could provide better models for testing new drugs and vaccines and predicting their safety and efficacy in clinical trials. These models could lower the number of toxic agents that appear in late-stage clinical testing, reduce the need to withdraw newly approved therapies from the market and minimize adverse events due to unidentified drug toxicities. Reviews Building Additional Complexity to In Vitro-Derived Intestinal Tissues These researchers discuss ways to make in vitro systems that are complex enough to model common intestinal illnesses comprehensively. For example, current models lack the nerves necessary for the typical gut contraction and relaxation that pushes food through the digestive tract. More biologically complete models of the human intestine could enable previously impossible cellular and molecular studies of normal and abnormal gut function. Such models also could provide a platform on which to look at the absorption and effectiveness of new drugs prior to clinical studies. And, principles learned in this study may be applicable to how nerves are formed and integrated in other in vitro organ systems. Building a Microphysiological Skin Model from Induced Pluripotent Stem Cells Model systems are needed that reliably represent both intact tissue and the interaction of a particular tissue with other systems in the body. Many drugs are designed for topical application to the skin, making it the first organ exposed. In addition, skin is often the first organ to show a reaction after system-wide drug delivery. The researchers discuss their strategy to use a type of adult human stem cell to develop an organ on a chip system that resembles and functions like human skin and can be used for analyzing drug interactions with the skin. Human Enteroids: Preclinical Models of Non-Inflammatory Diarrhea Researchers need a model of the human intestine that is both readily available and easy to use. Such a model could help scientists better understand the way the human intestine works and the functional changes in the intestine associated with diseases. This kind of model also would be a good platform for testing new drug therapies. The researchers describe their project to establish cultures of cellular structures that functionally represent each major section of the intestine. These structures, called enteroids, can be used as a preclinical model to study the functional changes associated with non-inflammatory (small intestinal) and inflammatory diarrheas and to develop drug therapies. Toward a 3-D Model of Human Brain Development for Studying Gene/Environment Interactions Project investigators aim to establish and characterize an in vitro model of the developing human brain so that they can test drugs and environmental agents. To be accurate, they need a model that is complex enough to show the interactions between different types of brain cells, such as glial cells and neurons. The model in this project is designed to assess the neurotoxic effects of various chemical agents on the unique processes that occur during human brain development. The researchers will use adult human stem cells derived from people with diverse genetic backgrounds, including those with neurodevelopmental disorders. Such a model will be a useful tool for research into central nervous system function and changes in function associated with diseases. Modeling Inflammation and Oxidative Stress in Gastrointestinal Disease Development Using Novel Organotypic Culture Systems These investigators are developing human cell-based tissue culture models of chronic conditions of the digestive tract, such as Crohn’s disease. These conditions share inflammation as a key driver in their development. With these model systems, the investigators plan to explore the effects of the body’s response to inflammation. These novel model systems could help scientists better understand chronic inflammatory disorders and foster the development of novel therapies and preventive strategies for digestive tract conditions. Three-Dimensional Osteochondral Microtissue to Model Pathogenesis of Osteoarthritis To develop drugs for osteoarthritis, researchers must first understand what causes the disease and how it develops. Project investigators are constructing an in vitro 3-D microsystem that models the structure and biology of the bone-cartilage complexes found at joints like the knee. They hope this will be the first step toward an improved in vitro model that can be used to predict the efficacy, safety and toxicology of candidate drugs to treat osteoarthritis. Novel In Vitro Respiratory Models to Study Lung Development, Physiology, Pathology and Toxicology Development of in vitro human lung tissue models would help bridge the current gap in knowledge of lung development, function and the changes lungs undergo due to disease or injury. Current in vitro lung models enable researchers to test hypotheses generated from human or animal studies directly in engineered human tissue models. These results already have been used to examine cell-based responses, physiological functions, unhealthy changes and even drug toxicity or responses. These investigators plan to create models with specific genetic profiles so they can test the importance of single gene products or pathways. In the future, model design will allow for linking of lung-on-a-chip devices to other organ systems, such as the heart, offering a more complete study of human drug responses. HeLiVa Platform: Integrated Heart-Liver-Vascular Systems for Drug Testing in Human Health and Disease This project team is developing an integrated platform with functionally connected blood vessel, liver and heart microtissues derived from a single line of adult human stem cells. This integrated system enables measurement of human physiological function, in real time, with readouts of all three systems. It also will be compatible with high-throughput analysis of responses to new drug therapy candidates, potentially transforming preclinical drug screening. In this paper, the investigators summarize their progress during the first year of the project. Microphysiological Systems and Low-Cost Microfluidic Platform with Analytics A functional multi-organ, human in vitro assay system would give researchers a more biologically accurate model for studying human disease and encourage basic and applied research. The system also would be of tremendous benefit in drug discovery and toxicology studies. This team describes its progress in developing a “body-on-a-chip” and the critical difficulties ahead as they continue development of these systems. Design Considerations for an Integrated Microphysiological Muscle Tissue for Drug and Tissue Toxicity Testing This research team has developed a 3-D model of the human skeletal muscle system that is connected to a vascular system consisting of a tissue-engineered blood vessel as part of a high-pressure arterial system. The muscle tissue reproduces the key functions of skeletal muscle in a living organism. This versatile system can be integrated with other organ systems and allows for noninvasive monitoring and assessment of tissue health response to drugs and poisons. All-Human Microphysical Model of Metastasis Therapy The investigators on this project are developing a human model of metastatic seeding (the spread of cancer cells throughout the body from the original tumor) that demonstrates metastatic growth. Scientists can probe this tiny bioreactor in real time to view a critical window into the abnormal physiology of metastasis and the pharmacology of metastatic tumor drug resistance. The model incorporates human breast cancer cells and liver cells — the liver is a major site of metastasis for a variety of cancers. This model of metastasis could provide information about how cancer cells spread and how they react to cancer drugs, enabling better clinical monitoring and improving clinical study design so that the effectiveness and safety of cancer treatments may be better understood. A Human Pluripotent Stem Cell Platform for Assessing Developmental Neural Toxicity Screening Researchers know surprisingly little about the hazards to human health posed by many of the tens of thousands of chemicals now in use. A primary reason for this knowledge gap is the lack of an affordable and effective way to test and screen chemicals. Project investigators review current methods of screening chemicals for toxicity in the nervous system and analyze these methods’ limitations. The project investigators are building a platform using adult human stem cells that scientists can use to test for developmental neural toxicity. Recreating the Female Reproductive Tract In Vitro Using iPSC Technology in a Linked Microfluidics Environment In this review, researchers describe development of a functional model of the female reproductive tract. This system produces hormones for reproductive function and cardiovascular, bone and sexual health, and it supports fetal development. The research team’s model uses a biological supporting structure to house the reproductive cells and a micro-scale circulatory system to support cell differentiation into multiple types, including epithelia, germ and somatic cells. This variety of female reproductive cells will all be developed from adult human stem cells. Human Induced Pluripotent Stem Cell-Based Microphysiological Tissue Models of Myocardium and Liver for Drug Development The project investigators provide a summary of the different approaches used to engineer in vitro constructs of human heart muscle and liver tissue, derived from adult human stem cells. The goal is to produce fully functional, 3-D heart and liver models on a chip. The investigators propose that these in vitro platforms can be used successfully for high-throughput screening for drug safety and effectiveness, reducing the need for often unreliable animal studies. Posted February 2014 | ||||||||
| 591 | Spotlight on Collaboration: A Journey From Biological Probes to Potential Therapeutics | Researchers studying the biology of diseases often use scientific tools called biological probes, which are small molecules that change biological processes or characteristics of a disease in some way. By using probes to increase or decrease the activity of a particular protein in a test called an assay, scientists can explore that protein’s role in health and disease. Sometimes, probes that produce a desired activity in an assay become a starting point for new therapeutics to treat disease. Traditionally, pharmaceutical and biotechnology companies have had the knowledge and extensive resources needed to develop successful probes.That story changed when what is now the NCATS Chemical Genomics Center (NCGC) was established in 2004. NCGC was the first center in a network of small molecule screening and medicinal chemistry optimization sites that produced small molecule probes as part of the NIH Common Fund’s Molecular Libraries Program.Over the past decade, NCGC’s scientists have worked closely with academic, nonprofit and biotech researchers on more than 300 collaborative probe development projects in virtually every area of biology and disease. Together, the partners have developed biological assays that are screened against hundreds of thousands of compounds using NCATS’ state-of-the-art, high-throughput (large-scale) screening robots. The identified compounds are then turned into probes via medicinal chemistry optimization.“We want to help investigators with a promising idea about important new biology or a novel way to reverse a disease state to develop the biological probes needed to test that idea,” said NCATS Director Christopher P. Austin, M.D. “Catalyzing the development of such innovative translational tools and technologies that speed development of new treatments for patients is NCATS’ mission.”As a demonstration of this mission in action, an NCATS-catalyzed project team has explored an enzyme family called lipoxygenases (LOX), which help the body metabolize fatty acids. What began as a project to explore the fundamental science has developed into a series of disease-focused collaborations among NCATS scientists and several U.S. research institutions. The team’s efforts culminated in the discovery of three novel small molecule chemical probes with the potential to treat diabetes, stroke and thrombosis.The chemical structures of small molecule probes used by scientists to understand the role of the lipoxygenase family of enzymes in health and disease.A Collaboration Is BornThe collaboration began in 2006 when Ted Holman, Ph.D., an enzymologist at the University of California, Santa Cruz, teamed with NCGC researchers David Maloney, Ph.D., Anton Simeonov, Ph.D., and Ajit Jadhav to develop molecular probes that would inhibit (block) the action of various LOX enzymes. Too much LOX activity may underlie a wide range of diseases, including asthma, heart disease, stroke and diabetes. By decreasing LOX activity in cell cultures and animal disease models, inhibitors could provide powerful tools for understanding the roles those enzymes play in health and disease.Until he joined forces with the NCGC team, Holman had trouble finding high-quality LOX inhibitors to use as molecular probes. Existing inhibitors were not specific enough, meaning that they acted on other enzymes in addition to the LOX target enzyme.Around that same time, a colleague told Holman about NCGC, where experts conducted screens using a method that involves testing compounds at multiple concentrations instead of just one. Screening at multiple concentrations allows for a higher probability of finding potential “hits,” which is particularly useful for difficult targets such as the LOX enzymes. Holman applied to work with the NCGC team through the Molecular Libraries Program.Through close collaboration over the past seven years, a joint project team made up of the Holman laboratory and NCGC team members successfully discovered and optimized several inhibitors for the LOX enzymes. Shortly after the team published initial results, biologists studying the role of LOX in disease were lining up, seeking collaborations with Holman and the NCGC team to use the LOX inhibitors for their studies. Up to that point, these scientists had never been able to find good LOX probes to adequately explore their diseases of interest. “What they needed was a small molecule tool to corroborate their molecular genetic data, to show that the LOX enzyme was involved in the diseases they were studying,” Holman said. “That’s the gold standard.”A New Tool for Solving Research ProblemsOne of these biologists was Jerry Nadler, M.D., at Eastern Virginia Medical School in Norfolk. From his work with a member of the LOX family called 12-LOX, using human tissue and mice, he had found that the enzyme’s activity was involved in the development of diabetes. Eliminating 12-LOX from mice ultimately protected them from diabetes.“The research had been going very well, but we were at a roadblock,” Nadler said. “To move the research forward, and possibly into the clinic, we needed a way to inhibit this enzyme. There was nothing available that was specific or good enough.”Nadler soon began working with two high-quality 12-LOX inhibitors (called ML355 and ML127) developed by Holman and the NCGC team. Nadler found that ML355 and ML127 protected pancreatic insulin-producing cultured cells from diabetic damage. The work led to funding from the Juvenile Diabetes Research Foundation, which will enable Nadler to treat diabetic mice with the inhibitor and assess its therapeutic potential. “It will be the first step on the way to clinical trials,” Nadler said.Broadening the Role of LOX InhibitorsMichael Holinstat, Ph.D., a biologist at Thomas Jefferson University in Philadelphia, also was examining the 12-LOX enzyme, but in a different condition: thrombosis, the formation of clots that can lead to heart attack and stroke. He had found evidence that 12-LOX was involved in the activation of platelets, the blood cells that form clots.Through his collaboration with Holman and the NCGC team, Holinstat used ML355 and other related compounds to show that 12-LOX is involved in platelet activation. Within five years, this work led to grants from the American Heart Association, National Institute of General Medical Sciences, and National Heart, Lung, and Blood Institute. This funding enables Holinstat to further explore the therapeutic potential of 12-LOX inhibitors to prevent thrombosis in at-risk patients.According to Holinstat, this success is due in no small part to the team-based approach at NCGC. “In this day and age, we can’t work in a lab by ourselves” he said. “I’m not a medicinal chemist. I don’t do high-throughput screening, so I would not have gotten to the point of identifying inhibitors for this enzyme.Likewise, NCATS and the Holman group are not disease experts. It’s a symbiotic relationship. [The collaboration] has allowed our lab to go in directions we had not otherwise been able to even think about.”An Expanding CollaborationKlaus van Leyen, Ph.D., a stroke researcher at Harvard, had found evidence that another member of the LOX family, 15-LOX-1, contributed to brain cell death and damage after stroke, but he needed an inhibitor to test his hypothesis. van Leyen began working with Holman and the NCGC team to develop an inhibitor for 15-LOX-1. They found one called ML351, and van Leyen began using it to study stroke.van Leyen found that ML351 reduces brain injury in mouse models of stroke. He continues to work with the team to optimize ML351’s effectiveness, so that one day soon it could be tested in humans. van Leyen has also received funding to study the therapeutic potential of LOX inhibitors in cardiac arrest.“To go from a random library of compounds you know almost nothing about and take it all the way to animal models of stroke has been fascinating,” van Leyen said. “This kind of collaboration has a synergistic effect, allowing us to move forward much more quickly than we could with any other type of approach.”From One Probe to Multiple Disease ApplicationsThe LOX teamwork exemplifies the kind of collaborative, innovative approaches to making translational research more efficient that are at the heart of the NCATS mission.“This collaboration has restructured my lab in incredible, positive ways,” Holman said. “That’s the power of NCATS: I run a small lab in a middle-sized university. NCATS resources have enabled me to play in a big field and stand taller than my stature would normally allow. NCATS was the catalyst for making it all happen.” Posted June 2014 | ||||||||
| 590 | Screening Platform Is a Launch Pad for Novel Treatment Combinations | More often than not, current medical treatments for a variety of diseases — including cancer, tuberculosis and brain disorders — involve administering more than just one drug, an approach known as combination therapy. There are thousands of approved and investigational drugs that can be combined in millions of possible pairings and dose variations. Clinicians often must make decisions based on trial and error, which is not optimal for the patient or the clinician. Enter NCATS, which develops, demonstrates and disseminates solutions to challenges just like this one. To fast-forward the drug combination research process, NCATS investigators recently developed a sophisticated combination drug screening platform. In the Jan. 27, 2014, early edition of the journal Proceedings of the National Academy of Sciences, the team published the results of a collaborative study with scientists from the National Cancer Institute (NCI). The study demonstrated how the platform can quickly narrow down a long list of potential drug combinations to find those with the most potential to help patients. Investigators chose a difficult-to-treat variety of diffuse large B-cell lymphoma (DLBCL), a type of blood cancer, as the model for the study. "NCATS is unique in its dedication to improving the process of translational research," said NCATS Director Christopher P. Austin, M.D., also an author on the paper. "This project demonstrates how the platform developed at our Center can take years off the process of testing new treatments for cancer and countless other diseases." Many Talents Develop and Disseminate a Powerful Tool Marc Ferrer, Ph.D., and Craig Thomas, Ph.D., research scientists in the NCATS Division of Preclinical Innovation (DPI), lead the multidisciplinary team that developed a high-capacity robotic platform to screen drug combinations. In just a couple of days, the robots can perform a drug screen that would take human researchers months to complete. Lesley Mathews Griner, Ph.D., a DPI research scientist, develops and oversees the tests (called "assays") that run on the platform. The system performs the automated assays using diseased cells that are placed on plates in tiny indentations called wells. Cells are treated in each well with a unique combination of drugs, and the assays reveal the effects of the drugs on each group of cells. The DPI team drew on diverse talents and experience in high-throughput screening and informatics to create this exceptionally powerful system. One feature that makes the platform stand out from previous combination drug screening efforts is the drug library it uses, called the Mechanism Interrogation PlatE (MIPE). All the drugs in the MIPE collection are relevant for clinical use in cancer and have mechanisms of action that scientists already understand. The observations of each drug pair’s effects on the target cells, coupled with the detailed knowledge about the compounds in the MIPE library, provide the researchers with insights into the interactions between various cellular processes. "This library will not only enable us to find compound combinations that can go rapidly into clinical trials, but also explore the biological processes that create the enhanced effect of a drug combination in a cell, leading to new drug targets," Ferrer explained. Another distinctive characteristic of the platform is that it enables investigators to test not just pairs of drugs but also many different doses of each drug. The robotic system does thousands of these mini-experiments on plates with up to 1,536 separate wells packed into just a few inches of space. Paul Shinn, who oversees compound management in DPI, led the team that used a new technology to create combinations of compounds for screening in these plates. Before the work led by Shinn’s team, performing this type of screen on 1,536-well plates was practically impossible. Rajarshi Guha, Ph.D., a DPI research scientist with expertise in informatics, led another technical team at DPI that developed an automated Web-based interface as well as an in-depth and highly sophisticated data analysis package to help researchers analyze the vast amounts of data produced. Finally, NCATS has given the broader scientific community access to the control software, interface and data generated in ongoing experiments. Any research group in the world can now build off the team’s work. "These results are hints that the broader community needs to further investigate," Thomas said. "Making the data public makes this possible." A Powerful Demonstration in Cancer For the cancer study, the DPI team collaborated with the NCI laboratory of Louis Staudt, M.D., Ph.D., a world-recognized DLBCL expert. DLBCL is the most aggressive and common type of adult lymphoma, a cancer of the white blood cells. The current standard of care for people with DLBCL is a combination of chemotherapies discovered through a long process of trial and error in the clinic. "Because chemotherapy only cures roughly half of individuals with DLBCL, we urgently need new curative therapies," Staudt said. The new screening platform helped the collaborators speed up the search for a second drug to combine with a promising new one called ibrutinib. The Food and Drug Administration already approved ibrutinib to treat two different forms of lymphoma. However, because the drug targets a molecular process that is a hallmark of DLBCL, it has demonstrated clinical efficacy as a single-drug treatment in this disease. The team systematically tested cancer cells from Staudt's lab using combinations of ibrutinib and 459 different drugs. Preliminary assays generated baseline data and revealed the most promising compounds to test in combination with ibrutinib. Additional assays tested the action of up to 10 different doses of each drug in combination. Ryan Young, Ph.D., a staff scientist in Staudt's group, confirmed the results of the screen in cancer cells. The final product was a short list of 30 drug pairs, many with unique mechanisms that target the specific molecular signature of the cancer cells tested. "A deeper analysis of each discrete combination will be key because we want to determine what would not only eradicate a cancer cell but kill it in a way that's not just toxic for the patient," Mathews Griner said. The Staudt group plans to publish more detailed information about the drugs’ molecular activity in an upcoming paper. Most important, these data provide a foundation for ongoing and future clinical trials. Staudt’s group also may pursue clinical trials of other suggested combinations. "We are fortunate to have a number of small molecules entering the clinic that target signaling and regulatory pathways that are relevant to DLBCL," Staudt explained. "However, we need guidance from these preclinical analyses to determine which of the many drug combinations to prioritize for testing in clinical trials." A New Approach Spreads Now, NCI is integrating the new screening platform into other Institute research. "We believe that use of this platform to identify novel, rational combinations of targeted therapies in a variety of tumor types will provide the foundation for therapeutic studies in the future," said Lee Helman, M.D., NCI scientific director for clinical research. NCATS is collaborating on combination drug screening projects with NCI groups interested in cancers of the kidney, pancreas, ovaries and other organs. The DPI team also has joined forces with scientists from the National Institute of Allergy and Infectious Diseases on malaria and tuberculosis projects. "This platform is a great example of NCATS' dedication to creating new solutions for problems in translational science, and it's proving its value for investigators at the Center, other NIH scientists and the rest of the research community," Austin said. With such investments in tools and expertise and a strong commitment to scientific collaboration, NCATS continues to accelerate and streamline the process of translational research to deliver new hope for patients. Posted February 2014 | ||||||||
| 589 | Pitt Researchers Work to Restore Function in Paralysis Patients | Five years ago, a cooperative multidisciplinary team of researchers at the University of Pittsburgh (Pitt) and its medical center set out to tackle an important translational research goal: Restoring function for those who can’t move. Now, for the first time, breakthrough brain-computer-interface research published in the Lancet in December 2012 provides hope to nearly 6 million paralyzed individuals and another 1.7 million amputees nationwide. The collaboration relied on help from four federal agencies ― NIH, the Department of Defense (DoD), the Department of Veterans Affairs (VA), and the U.S. Food and Drug Administration (FDA) ― along with support by a private foundation, two academic research centers and a private company. Supporting such teams to overcome roadblocks in the translational research process and turn basic discoveries into tangible health improvements is exactly what NCATS strives to accomplish. "The problems don’t end when you build a robotic arm or better computer-access," explained Michael Boninger, M.D., professor and chair of the Department of Physical Medicine and Rehabilitation in the Pitt School of Medicine. "The problem has always been how someone with limited ability can control the device." Boninger and his co-investigator, Andrew B. Schwartz, Ph.D., a Pitt neuroscientist, agreed: "If we could get the technology into humans, we could have them playing the piano," he recalled saying to Boninger at the start of the project. It was with this patient perspective in mind that the team set out to make the technology work. From the beginning, it was made possible by the Pitt Clinical and Translational Science Institute (CTSI), supported by NCATS' Clinical and Translational Science Awards (CTSA) program. "There is a really collaborative group of researchers at Pitt. It's a critical mass," said Boninger. "And then there’s the structure that supported all of that: the CTSI." The Pitt CTSI, which is one of about 60 CTSA-funded academic research centers dedicated to strengthening the entire spectrum of translational research, facilitated this work by providing training, regulatory expertise and pilot research support. Turning a Possibility into a Reality As explained in the Lancet study, the Pitt team implanted electrodes into a paralyzed patient’s brain so they could pick up her brain signals while she imagined moving her hand and arm. A computer interface translates the signals, allowing her to control with her mind the prosthetic arm and hand in a full range of motion, including the ability to grasp objects. The Pitt CTSI paved the road to this accomplishment by providing initial research funding and helping to assemble the diverse team required. In 2007, bioengineer Wei Wang, M.D., Ph.D., joined Boninger's department. Wang’s previous research helped discover changes in brain signals when people moved their fingers and hands in different directions. Wanting to use this insight to help paralyzed patients, Wang met with his new colleagues at Pitt to discuss ways to push the work forward. Representatives of the CTSI and the head of the Pitt Institutional Review Board (IRB) Office were in attendance to help expedite the translation of this idea into the clinic. "From the very beginning, our stated goal was a clinical trial," Elizabeth Tyler-Kabara, M.D., Ph.D., remembered. The Pitt CTSI awarded a Translational Tool Pilot Project grant to Wang and his new research partner, neurosurgeon Tyler-Kabara. The grant required a multidisciplinary team approach, formalizing the existing collaboration between neurologists, neurosurgeons, neurobiologists, bioengineers and physicians. On the Road to Translation Using a surgically implanted micro-electrocorticography (ECoG) electrode grid, the team began by mapping the association between brain waves and arm and hand movement in patients already scheduled for epileptic seizure monitoring. Once they had mapped the signals, the team programmed a computer to interpret the results and convert them into movement in computer games. The volunteer epilepsy patients soon were able to use their thoughts to control movement of a cursor or an animation character on a computer screen. Funding from NIH’s National Institute for Neurological Disorders and Stroke (NINDS) and the DoD’s Defense Advanced Research Projects Agency (DARPA) enabled the Pitt team to pair a brain-computer interface with a dexterous robotic arm. Dr. Schwartz had taught monkeys to feed themselves using their thoughts to control first a simple arm and gripper, and later a human-like arm developed at the Johns Hopkins University Applied Physics Laboratory. The next step was to test the technology in people who were paralyzed. The First Human Trial Based on the CTSI-funded mapping work, Wang received a critical KL2 Mentored Research Investigator Training Award in 2010. Naming Boninger and Schwartz as his senior mentors, the grant enabled Wang to take the lead on a new clinical trial combining the mapping data from his pilot work with the ECoG technology, already in clinical use with epilepsy patients, and put the device into a paralyzed patient. "The KL2 award really provides the structure to develop this kind of work," Wang said. "I could bring my questions to team members from varied backgrounds and disciplines.” Work with the first patient began in August of 2011. The patient learned to manipulate objects with the robotic arm using only his thoughts. The soon-to-be-published data from this experiment actually showed changes in brain patterns over time as the patient became better at the tasks. The patient's brain appeared to be learning — and so was the research team. Study participant Tim Hemmes (right) reaching out to his researcher, Wei Wang, M.D., Ph.D. (left), using a brain-controlled prosthetic arm. Also pictured: Research team member Jennifer L. Collinger, Ph.D. and Katie Schaffer. (University of Pittsburgh Medical Center Photo) Experience Pays Off Schwartz and Boninger now lead a year-long experiment with their second human patient using a different technology from the earlier ECoG device. This smaller, more sensitive electrode grid from Blackrock Microsystems penetrates into the brain rather than sitting on its surface. Before the experiment could begin, the Pitt IRB and the FDA had to give permission to test the device in humans. DARPA brought the FDA into discussions immediately, fast-tracking this permission step. With help from regulatory experts at the Pitt CTSI and championed by Dr. Jennifer Collinger, another bioengineer and faculty in Boninger's department, the study team wrote the FDA application and created a protocol to pursue the research in paralyzed humans. Both were approved in only nine months; typically this is a process that can take years. Armed with the surgical input from the previous study and the monkey data using the robotic arm, their protocol and the FDA application were solid. "Nothing about it surprised the FDA because we had been having discussions with them all along," said Boninger. Because of the technology’s potential to help amputee soldiers, the group was able to garner funding from both DARPA and the VA. "Once you have this multidisciplinary collaboration in place," Wang explained, "the diversity of skills allows your research team to reach out to different agencies for funding." With the new setup installed in her brain, the study volunteer moved the robotic arm with only her thoughts less than one week after surgery. After 13 weeks of controlling the arm with her thoughts, the process was routine. Her goal was to take a bite of chocolate. The fact that she could and did was a huge accomplishment not only for her but also for the study team. Looking Ahead: Applying the Technology The team continues to develop both technologies in parallel. "We want to be able to make this work for the long term," said Boninger, "but we have lots of science to do first. That is why we think it is critical to continue to investigate both technologies." "We already have seen how well this works in a patient with a neurodegenerative disease," said Tyler-Kabara. "That opens the door for applications that may help those with spinal injuries, amputees and those with cerebral palsy. The population that could benefit from this technology is limited only by our imagination." Schwartz is quick to insist that this is still a research tool. "It is not robust enough to be used widely, but we could have patients using it at home in a year or two in a research protocol," he said. The goal is a fully implanted device that gives patients feeling and control that others can’t see. To make this a real treatment alternative for patients, the team continues to rely on CTSI resources. They are using the Pitt CTSI Research Participant Registry to help them find study volunteers. This independent registry has more than 38,000 individuals who have indicated a willingness to consider participation in clinical trials. The next big steps in making this available for patients will be getting FDA approval and then commercialization. "This will involve new initiatives, and we will need help," said Boninger. "We know we can rely on CTSI expertise to get us there." Posted January 2013 | ||||||||
| 588 | RNAi Screen for Modulators of Topoisomerase 1 Poisons in Breast Cancer Cells | Breast cancer is the second most common cancer among women in the United States. According to the Centers for Disease Control and Prevention, in 2010, more than 200,000 women were diagnosed with breast cancer, and nearly 41,000 women died from it. A promising approach to treating breast and other cancers is combination therapy, in which drugs with different actions are given together to enhance their anti-cancer effects. These investigators are using small interfering RNAs (siRNAs), which selectively and systematically inhibit the activity of genes, to look for genes in breast cancer cells that can be targeted in combination with an existing class of cancer drugs, called Topoisomerase 1 poisons (TOP1). This research could lead to the development of new drugs to be used in combination with TOP1 poisons for treating breast and other cancers. Scientific Synopsis Combination therapy is an effective and promising approach toward the treatment of cancer. The investigators are conducting large-scale RNAi screens for novel targets that synergize with TOP1 inhibitors. TOP1-targeted drugs (topotecan and irinotecan) represent an important class of drugs for the treatment of colorectal, ovarian, lung and pediatric cancers. The Pommier laboratory at the National Cancer Institute recently discovered a novel class of non-camptothecin TOP1 inhibitors, the indenoisoquinolines. The indenoisoquinolines have overcome limitations of the camptothecins in preclinical models and are among the most advanced anticancer drugs in the non-camptothecin TOP1 inhibitor class. Two indenoisoquinolines are in clinical trials at the NIH Clinical Center in Bethesda, Maryland. The aim of this project is to use a large-scale siRNA screen to uncover novel pathways that determine the efficacy of TOP1 inhibitors. The investigators are using the triple-negative breast cancer cell line MDA-MB231 cells (previously validated as very effective for siRNA screen) and the clinically-relevant indenoisoquinoline TOP1 inhibitor NSC 725776 (LMP-776) and NSC 724998 (LMP-400) for the high-throughput screen at the NCATS Chemical Genomics Center. Hit validation is being performed using experiments in additional cell lines, and specificity is being determined by evaluating active genes in the context of non-TOP1 inhibitors (e.g., taxol and etoposide). These efforts will help discover new genomic biomarkers to predict the activity of TOP1 inhibitors and personalize therapies in cancer patients. Identification of new pathways may also lead to the development of novel therapies using small molecules or biologicals for the treatment of cancers in combination with TOP1 inhibitors. Lead Collaborators National Cancer Institute Yves Pommier, Ph.D. Natasha Caplen, Ph.D. National Center for Advancing Translational Sciences Madhu Lal-Nag, Ph.D. Public Health Impact This study will reveal determinants of TOP1 poison efficacy, providing potential biomarkers for personalized medicine and identifying putative targets for combination therapies. Publications Martin SE, Wu ZH, Gehlhaus K, et al. RNAi Screening Identifies TAK1 as a Potential Target for the Enhanced Efficacy of Topoisomerase Inhibitors. Curr Cancer Drug Targets, 2011;11(8):976-986. Zhang YW, Jones TL, Martin SE, et al. Implication of Checkpoint Kinase-Dependent Up-regulation of Ribonucleotide Reductase R2 in DNA Damage Response. J Biol Chem, 2009;284(27):18085-18095. Outcomes Among other pathways and targets, these efforts have identified TAK1 and other related genes as important regulators of TOP1 poison-mediated apoptosis. Project Details Screening Protocol to Identify Determinants of TOP1 Poison Activity in Breast Cancer Cells After optimization of transfection and assay conditions, a druggable genome siRNA library targeting H 7,000 human genes (4 siRNAs per gene) was screened both in the absence and presence of TOP1 poisons. Transfections were performed in MDA-MB-231 breast cancer cells. Knockdown was allowed to proceed for 48 hours before treatment with TOP1 poison for an additional 72 hours. Informatic analysis of this data identified more than 100 putative sensitizers. Rigorous follow-up resulted in the confirmation of numerous confident hits, including known DNA repair related genes such as ATR. Ongoing studies are being performed with validated targets in additional cell lines and in the context of non-TOP1 inhibitors (e.g., taxol and etoposide). Follow-up dose response analysis with several siRNAs confirms that the down-regulation of ATR significantly enhances TOP1 poison activity in MDA-MB-231 breast cancer cells. | ||||||||
| 587 | RNAi Screen for Genes that Prevent DNA Re-Replication | Most cells in the human body have two sets of 23 chromosomes, one from each parent. Chromosomes are single pieces of coiled DNA containing many genes. Chromosomes are replicated in a tightly controlled process during cell division so that each chromosome is replicated only once. DNA re-replication is an abnormal form of replication that produces a mixture of partially and fully completed chromosomes. This results in cells with repeated DNA content of between four and eight sets of chromosomes. To better understand how over-replication occurs, the investigators on this project will look for genes that prevent this process. Using small interfering RNAs (siRNAs), which selectively and systematically inhibit gene activity, the researchers will screen for genes that, when silenced, lead to over-replication of DNA in colorectal cancer cells. The study may help scientists better understand DNA re-replication and identify new treatment targets for colorectal and other cancers, since cancer cells may be particularly vulnerable to triggering re-replication. Scientific Synopsis Genome duplication in mammals normally occurs only once each time a cell divides. This restriction is circumvented on rare occasions during animal development to allow certain cells to differentiate into specialized polyploidy cells containing multiple copies of their nuclear genome. Such cells are stable, but no longer proliferate. Otherwise, agents that cause mammalian cells to re-replicate their DNA before completing mitosis cause replication forks to stall and DNA strands to break. These events trigger DNA damage response pathways and eventually, apoptosis. Such events can also lead to the progression of human disease, especially cancer. Unfortunately, the mechanisms that prevent over-replication of DNA during proliferation of human cells are still poorly understood. Therefore, the goal of this project is to identify genes that contribute to preventing either DNA re-replication or the induction of polyploidy in human cells. To this end, we are screening for siRNAs that induce over-replication in human cancer cells. Identified genes are being screened further in a panel of both cancer and normal cells to identify cancer-selective targets. These efforts will not only illuminate genes associated with this poorly-mapped cellular process, but identify new molecular targets for clinical development. Screen for DNA Re-Replication in Cancer Cells Lead Collaborators Eunice Kennedy Shriver National Institute of Child Health and Human Development Mel Depamphilis, Ph.D. George Washington University Wenge Zhu, Ph.D. National Center for Advancing Translational Sciences Madhu Lal-Nag, Ph.D. Public Health Impact This study will reveal determinants of DNA re-replication and identify putative strategies for the treatment of cancer. Publication Zhu W, Depamphilis ML. Selective killing of cancer cells by suppression of geminin activity. Cancer Res, 2009;69(11):4870-4877. Outcomes These studies have confirmed the acute importance of geminin in the replication of cancer cells and identified additional genes, which are the subject of ongoing follow-up studies. Project Details The transfection of siRNA targeting geminin into HCT-116 colorectal cancer has previously been shown to induce a significant amount of DNA re-replication. Based on these findings, we conducted preliminary studies to determine whether these observations would translate to a high-throughput amenable RNAi assay. As shown in the figure, the transfection of an siRNA against geminin induced a significant amount of re-replication in HCT-116 cells, 72 h post-transfection. Furthermore, a comparison of negative control and geminin siRNA transfected cells indicated a good assay Z"-factor of 0.5 in 384 well plates. Pilot screens comprising two independent screens of an siRNA library directed against the human kinome also showed good correlation. We have now completed a comprehensive genome-wide screening campaign. Identified genes are the subject of intense validation and secondary assays. The transfection of an siRNA targeting geminin induced a significant amount of re-replication in HCT-116 cells, 72 hours post-transfection. Furthermore, a comparison of negative control and geminin siRNA transfected cells indicated a good assay Z"-factor of 0.5 in 384-well plates. | ||||||||
| 586 | RNAi Screen for Genes Involved in the Recruitment of Parkin to Damaged Mitochondria | Parkinson’s disease is a movement disorder characterized by tremor, stiffness of limbs, slow movement, and impaired balance and coordination. The symptoms result from death of cells in the brain that make a chemical important for movement. Studies suggest that this cell death may be caused by damage to a structure within cells crucial for cell functioning: the mitochondria. Soon after mitochondria are damaged, a protein called Parkin helps repair them and prevents cell death. The investigators will screen for small interfering RNAs (siRNAs), which selectively and systematically inhibit gene activity, to find genes that enable Parkin to respond to mitochondrial injury. The information gained from this study could help scientists find drugs that enhance this repair response and better treat neurodegenerative diseases such as Parkinson’s. NIH scientists used RNA interference to find genes that interact with parkin (green), a protein that tags damaged mitochondria (red). Mutations in parkin are linked to Parkinson’s disease and other mitochondrial disorders. (NINDS Photo/Youle Laboratory) Scientific Synopsis An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson's. Following mitochondrial damage and the loss of mitochondrial membrane potential, the proteins PINK1 and Parkin coordinate a rapid response that can attenuate cell death. Given that enhancing this response may help elude the consequences of mitochondrial dysfunction, genes associated with the localization of Parkin to damaged mitochondria could serve as important drug targets. Unfortunately, the exact mechanism of this response is poorly understood. The aim of this study is to use genome-wide siRNA screens to identify genes involved in the recruitment of Parkin to damaged mitochondria. Screening has yielded many candidates and a number of these have been extensively validated by the Youle lab at the National Institute of Neurological Disorders and Stroke. These efforts will provide a better understanding of mitochondrial quality control, and may inform on therapeutic targets for neurodegenerative diseases such as Parkinson’s. Lead Collaborators National Institute of Neurological Disorders and Stroke, Bethesda, Maryland Richard Youle, Ph.D. George Washington University, Washington, D.C. Wenge Zhu, Ph.D. Public Health Impact These efforts will provide a better understanding of mitochondrial quality control and may inform on therapeutic targets for neurodegenerative diseases such as Parkinson’s. Publication Hasson, S.A., Kane, L.A., Yamano, K., et al. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature, Nov. 24, 2013. Outcomes These studies have implicated numerous genes in the recruitment of Parkin to damaged mitochondria. Follow-up studies have further validated several genes, including TOMM7, which was found to be essential for stabilizing PINK1 on the outer mitochondrial membrane following damage. Project Details Hela cells stably expressing GFP-Parkin and a mitochondrial-targeted red fluorescent protein are transfected with siRNA duplexes in 384-well plates. After a 48 hour siRNA knockdown, the proton ionophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP) is added to each well to induce rapid mitochondrial depolarization. Following bulk mitochondrial depolarization in all cells, GFP-Parkin translocation to damaged mitochondria is allowed to progress for 2.5 hours before cells are fixed. The degree of Parkin translocation to mitochondria is then assessed by high-content acquisition and analysis. Screen for Genes Involved in the Recruitment of Parkin to Damaged Mitochondria Left image thumbnail: GFP-Parkin is translocated to the site of damaged mitochondria. Right image thumbnail: Translocation is blocked through siRNA knockdown of PINK1 | ||||||||
| 585 | Patient Registries | A registry is a systematic collection of standardized data about a group of individuals. Two primary types of registries are relevant to translational science and the mission of NCATS: patient registries and contact registries. Patient registries contain clinical data about individuals who have a specific condition or type of disease as well as contact and demographic information, such as age and gender. Some registries are defined and led by patient advocacy groups for specific or similar disease diagnoses and to track the course of a condition over time both with and without treatment. Researchers use this information to evaluate specified patient outcomes for a particular disease or condition. The Rare Diseases Registry (RaDaR) program, formerly known as the Global Rare Diseases Registry Data Repository (GRDR) program, aims to define best practices for patient registries. RaDaR also strives to identify and adopt standards to support high-quality registries for rare diseases therapeutics development. To achieve these aims, RaDaR staff will: identify, develop and validate data standards, data collections and data sharing practices that can be used across the rare disease registry community; develop best practices for building high-quality registries able to support therapeutics development; and make these best practices and standards broadly available and easily accessible to the rare disease community. Setting up a patient registry is significantly more involved and costly than having a contact registry for multiple reasons. For example, the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule mandates the way in which protected health information is used or shared. To enable the flow of health information needed to provide and promote high-quality health care and research while remaining HIPAA compliant, each individual is assigned a unique reference code and all personally identifiable information is removed. |
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