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| 561 | Freedom of Information Act Requests (old) | The Freedom of Information Act (FOIA), 5 U.S.C. 552, provides individuals with a right to access to records in the possession of the federal government. The government may withhold information pursuant to the nine exemptions and three exclusions contained in the Act. If you have questions regarding FOIA requests pending with NCATS or questions specific to NCATS records, please contact Marianne Manheim, NCATS FOIA Coordinator, by phone (301-496-9737) or email (nhlbifoiarequest@nhlbi.nih.gov). For more details about the types of information you can request through FOIA, or to submit a FOIA Request with NIH, visit the National Institutes of Health FOIA Page. | ||||||||
| 560 | NCATS Science Featured at 28th NIH Research Festival | Researchers from NCATS and other NIH Institutes and Centers recently gathered at the 28th NIH Research Festival to share insights on important scientific advances made by intramural investigators. The annual event took place Sept. 22 – 24, 2014, at the NIH Clinical Center in Bethesda, Maryland.NCATS research scientist Marc Ferrer, Ph.D., and National Cancer Institute staff scientist Matthew Hall, Ph.D., co-chaired a concurrent symposium at the festival called "Assays to lead the way: High-throughput screening and probe discovery at the NIH." Attendees included Michael Gottesman, M.D., NIH deputy director for intramural research, and many others interested in ways to collaborate with NCATS scientists and access the Center’s high-throughput robotic screening capabilities. The robots can help investigators translate their work into potential therapeutics to treat disease or to generate molecular "probes" to better understand disease biology.As part of the symposium, Anton Simeonov, Ph.D., acting deputy director of the NCATS Division of Preclinical Innovation, discussed collaborative opportunities for intramural researchers in early drug discovery, and NCATS scientist Craig Thomas, Ph.D., presented innovative approaches Center researchers have developed to identify small molecule therapeutics and optimal drug combinations to treat diseases such as cancer and malaria.In addition, investigators from the National Human Genome Research Institute (NHGRI) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) discussed the progress of existing research projects with NCATS. Ellen Sidransky, M.D., senior investigator in the Medical Genetics Branch at NHGRI, talked about her work with Center researchers to identify lead compounds and develop robust models for Gaucher disease. Sidransky also discussed the project’s relevance to neurological disorders that may share underlying molecular defects with Gaucher, such as Parkinson’s disease. Jake Liang, M.D., chief of the Liver Disease Branch at NIDDK, described a collaborative effort with NCATS researchers around potential therapeutics for the hepatitis C virus."The talks complemented one another more than we could possibly have anticipated and conveyed to a new audience the possibilities for assay development and high-throughput screening for the intramural community," Hall said.More than 20 NCATS scientists co-authored posters about recent research at sessions throughout the festival. Posters focused on rare diseases, infectious diseases, cancer, chemical toxicology and multidrug-resistant bacteria. Click on each title below for details:Drug repurposing screen to identify new therapeutics for the Carbapenem-resistant Klebsiella pneumoniaAuthors: S. Dai, W. Sun, R.A. Weingarten, P. Shinn, J.C. McKew, K.M. Frank, W. ZhengHTS of IDH1 R132H leads to identification of a potent inhibitor of IDH1 R132H capable of reducing 2-hydroxyglutarate production in U87-MG glioblastoma cellsAuthors: M.I. Davis, R. Pragani, S. Gross, J. Popovici-Muller, K. Straley, W. Lea, Z. Li, L. Dang, M. Shen, M.B. Boxer, A. SimeonovQuantitative profiling of environmental chemicals and drugs for farnesoid X receptor activityAuthors: C.W. Hsu, J. Zhao, R. Huang, J.H. Hsieh, J.T. Hamm, X. Chang, K.A. Houck, M. XiaEvaluation of drug efficacy in a cell based Niemann Pick type C disease model using cells derived from patient iPS cellsAuthors: Y. Long, R. Li, M. Wang, S. Dai, M. Swaroop, J.C. McKew, W. ZhengNew antimalarial agents and drug targets identified from a screen against plasmodium falciparum gametocytesAuthors: W. Sun, T.Q. Tanaka, C.T Magle, W. Huang, N. Southall, R. Huang, S.J. Dehdashti, J.C. McKew, K.C. Williamson, W. Zheng Posted September 2014 | ||||||||
| 559 | Accessibility | NCATS makes every effort to ensure that the information available on this website is accessible to all. If you use special adaptive equipment to access the Web and encounter problems when using this website, send an email to info@ncats.nih.gov with a description of what you would like to access. Please be as specific as possible when describing the information you seek. NCATS staff will attempt to provide the information in a suitable format. For NIH employees who need assistance with accessibility, contact the equal employment opportunity officer at your institute or center. To learn more about the regulations governing the accessibility of federal electronic information products, visit the United States Access Board or the federal Section 508 website. Thank you for using the NCATS website. | ||||||||
| 558 | NCATS Researchers Propose Innovative Approach to Test Drugs in Rare Diseases | Developing effective treatments is a slow and costly process, and more than 80 percent of investigational drugs tested in clinical trials fail. Discovering treatments for rare diseases can be even more challenging because the small numbers of patients with these diseases make it difficult to find enough people who can participate in clinical trials. The small numbers of rare disease patients also make gathering information about the diseases difficult. As a result, scientists often know little about the symptoms and biology of these conditions, which adds to the complexity of designing drug studies. Additionally, pharmaceutical companies may find it difficult to justify the cost of developing drugs for such small markets of rare disease patients. There are about 7,000 diseases that affect humans, and treatments are available for fewer than 1,000. That's about 6,000 untreatable diseases. At the current rate of transition from untreatable to treatable, which amounts to a handful of drugs approved each year, it will take more than 1,000 years for every disease we know of now to be treatable. "NCATS' mission is to get more treatments to more people more quickly," said NCATS Director Christopher P. Austin, M.D. "One way NCATS does this is to approach the universe of diseases in a holistic way, focusing on finding connections among conditions that at first glance may seem unrelated." In a paper published in the June 6, 2014, issue of Nature Biotechnology, NCATS scientists present an approach to combat the odds in just this way: Pursue treatments by targeting common molecular mechanisms across multiple rare diseases. "It's a proposal for a new way to test drugs and develop better treatments for rare disease patients," said P.J. Brooks, Ph.D., a program director in NCATS' Office of Rare Diseases Research (ORDR) and lead author of the paper. Currently, scientists design clinical trials by testing one drug in a group of patients with a single disease. In other words, potential treatments currently are tested in only one disease at a time. Instead, the authors say, a more efficient method would be to group patients whose rare diseases are caused by the same type of genetic abnormality and then treat them all with a drug that is designed to address that problem. For example, several rare diseases are caused by a type of genetic change called a nonsense mutation, which prevents the body from making full-length proteins. Another type of mutation, a missense mutation, can cause abnormal protein folding and also underlies multiple rare diseases. Either type of mutation can result in cystic fibrosis, a life-threatening lung disease; Gaucher disease, which affects the blood-forming organs, bones and nervous system; or Tay-Sachs disease, a neurodegenerative disorder. Although these diseases differ in their characteristics and affected genes, many people with the conditions have one of the two types of mutations. Therefore, drugs that correct missense or nonsense mutations could be tested in all three diseases. Using this approach, each candidate drug for a specific type of mutation could be tested in a single clinical trial for all three diseases. In the standard clinical trial approach, each drug would be tested separately in each disease, tripling the number of trials needed. "Research based on shared molecular mechanisms would enable scientists to classify thousands of diseases into a smaller number of categories," Austin said. "This method could reduce the time and costs associated with clinical trials, enhancing the efficiency and pace of getting drugs to rare disease patients." Targeting missense and nonsense mutations are just two examples. Using DNA sequencing and other genomic technologies — combined with basic research findings to identify disease-related mutations — will continue to help scientists identify many other types of common molecular mechanisms underlying traditionally distinct diseases. Already, researchers are demonstrating the feasibility of this new approach. A group of scientists across 26 U.S. hospitals, as part of the Children’s Oncology Group supported by the National Cancer Institute, is conducting a treatment study of four pediatric cancers. Each cancer affects different parts of the body, including the blood, lungs and brain. However, mutations that lead to too much activity of the ALK gene underlie each of the four cancers in some patients. The scientists are testing the effectiveness of a drug targeting the ALK gene product to treat all four diseases. Carrying out this approach in clinical trials of rare diseases ideally would happen through a collaborative network of institutions where multiple scientists are studying different rare diseases, Brooks explained. This way, researchers could cooperate, share data and ensure high quality of studies more easily. The Rare Diseases Clinical Research Network, coordinated by ORDR, already is taking this approach. Brooks hopes that the proposal begins a discussion among rare disease researchers, patient groups and industry about better ways to develop treatments for patients with rare diseases. Posted June 2014 | ||||||||
| 557 | NCATS Research Team Identifies Possible Treatment for Niemann-Pick Type C1 | Translational research is a team sport. To help streamline the scientific process, NIH's NCATS facilitates team-based collaborations among researchers who have varied areas of expertise. One such collaboration includes government, academic scientists, the pharmaceutical industry and patient support groups dedicated to finding potential treatments for a rare disease known as Niemann-Pick type C1. The disease causes lipids such as cholesterol to accumulate primarily in the cells of the brain, impairing movement and leading to seizures, dementia and slurred speech, among other symptoms. The majority of patients die in their teenage years. The Niemann-Pick type C1 research team, which includes scientists from the NCATS Division of Preclinical Innovation, recently showed that patient skin cells treated with a form of vitamin E, called delta-tocopherol, had lower accumulation of cholesterol. The team’s findings, published in the Nov. 16, 2013, issue of the Journal of Biological Chemistry, represent another potential ingredient in a treatment cocktail for Niemann-Pick type C1. "The Niemann-Pick type C1 research collaboration is a great illustration of the NCATS approach, which combines individual initiative and teamwork to deliver results that no one group can do alone," said Christopher Austin, M.D., director of NCATS. The Niemann-Pick type C1 team includes scientists from NCATS, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Human Genome Research Institute. In addition, there are academic collaborators from Washington University in St. Louis, Albert Einstein College of Medicine in New York City and University of Pennsylvania in Philadelphia as well as a pharmaceutical industry partner, Janssen Research & Development, LLC. The academic partners are funded through the Support Of Accelerated Research (SOAR), which was established by patients and their parents to find a cure for Niemann-Pick disease. The Ara Parseghian Medical Research Foundation contributed funding as well. The collaboration began in 2008. Each team member brings a set of skills, knowledge and expertise that contributes significantly to the project, from cell biology to physiology to NCATS’ extensive drug discovery and preclinical drug development capabilities. The group’s first step was to create an biological assay (or testing system) for Niemann-Pick type C1. The assay was screened against the NCATS Pharmaceutical Collection, which at the time included about 2,800 approved drugs, to identify drugs that had activity in Niemann-Pick type C1 cells. The hits included delta-tocopherol and cyclodextrin. The research team continued to develop cyclodextrin through NCATS' Therapeutics for Rare and Neglected Diseases (TRND) program, and the potential treatment is now undergoing evaluation in clinical trials. From left to right: a healthy control cell, an NPC cell, an NPC cell treated with delta-tocopherol and an NPC cell treated with alpha-tocopherol. The image shows that treatment of NPC cells with delta-tocopherol alleviates the disease characteristics in the NPC cell. "At first, we did not pursue delta-tocopherol because of our focus on developing cyclodextrin, which looks quite promising as a potential treatment for Niemann-Pick type C1," said Wei Zheng, Ph.D., TRND biology lead and co-author of the delta-tocopherol paper. "Eventually, we followed up on delta-tocopherol and found it has a profound effect on Niemann-Pick cells and had some potential to be developed as a possible treatment." The researchers treated skin cells with delta-tocopherol and observed that it seemed to clean up lipids that had accumulated in the cells via a process called lysosomal exocytosis, which helps cells export unwanted materials. They also tested the alpha form of vitamin E, commonly sold in stores, and found that although it too helped reduce cholesterol and lipids in the cells, it had a much weaker effect than delta-tocopherol. As the research continued, the team found that delta-tocopherol treatment produced similar results in cells of other lysosomal storage diseases, such as Batten, Fabry, Farber, Niemann Pick type A, Sanfillipo type B, Tay-Sachs and Wolman diseases. The unique effect and mechanism of delta-tocopherol on Niemann-Pick and the other lysosomal storage diseases reveals a new direction of future drug development for a class of drugs that target lysosomal exocytosis. Not much is known about the mechanism by which vitamin E works, although the antioxidant effect has been extensively reported. The researchers found a clue when looking at previous findings suggesting that Niemann-Pick type C1 is associated with reduced calcium levels in lysosomes, an organelle in cells that breaks down waste materials. According to study authors, an increase in calcium in cells triggers a variety of cellular responses that reduces lipid accumulation in a disease model. "The researchers tested this idea and found that delta-tocopherol indeed stimulated a calcium response in the Niemann-Pick cells, which enhanced lysosomal exocytosis," said John McKew, Ph.D., acting director of NCATS’ Division of Preclinical Innovation. "This knowledge is important for understanding Niemann-Pick disease and also may be valuable for studying the benefits of vitamin E." Researchers have a lot of work to do before delta-tocopherol can be considered as a viable treatment candidate for lysosomal storage diseases. For instance, the researchers know that delta-tocopherol is metabolized quickly and does not penetrate the blood-brain barrier at a concentration at which its therapeutic effects are needed. To address this obstacle, NCATS chemists have modified the delta-tocopherol molecule to increase its concentration in the blood stream and its ability to penetrate the blood-brain barrier. Improvements of these properties are crucial for the development of the next generation of compounds for treatment of Niemann-Pick type C1. "The important thing about the delta-tocopherol project is that the team did not give up on it, and the molecule is showing great promise again," said Jonathan Jacoby, a rare disease advocate who has been following the team's progress. "I'm optimistic [about finding an NPC treatment] because there is a real pipeline of potential therapies as a result of this collaboration." Posted February 2013 | ||||||||
| 556 | NCATS and Johns Hopkins Researchers Identify New Therapeutic Strategy for Eye Diseases | Understanding of the causes and characteristics of many diseases has improved dramatically over the past several decades, but in most cases, new interventions based on this understanding have not kept pace. NCATS focuses on ways to speed the development of diagnostics and therapeutics to unlock the promise of science for patients. The NCATS approach — which is based on innovation in how science is done as well as what is done — now has led to dramatic success for a project focused on degenerative diseases of the retina. Retinal diseases, including glaucoma, retinitis pigmentosa and age-related macular degeneration (AMD), damage the vision of millions of people worldwide. The work was published in the March 5, 2013, issue of the Proceedings of the National Academy of Sciences (PNAS). Like many other diseases, glaucoma typically has limited or no treatment options. Although researchers possess a breadth of knowledge about the cause of glaucoma, they have struggled to identify molecular targets that could lead to new and more effective treatments. Scientists at NCATS are experts at this first step in the translational process, determining targets for disease intervention. However, to be effective in addressing specific diseases, NCATS’ translational expertise is matched with expertise in those diseases — thus, the fundamental NCATS principle that "translation is a team sport." NCATS custom-assembles a team for every project, each built to solve a particular roadblock to translation. In this case, the team included NCATS and the Johns Hopkins School of Medicine in Baltimore. Don Zack, M.D., Ph.D., a glaucoma specialist and molecular biologist at Hopkins’ Wilmer Eye Institute, had extensive knowledge and robust animal models of retinal degenerative diseases. He and his team, which included Derek Welsbie, M.D., Ph.D., Zhiyong Yang, M.D., Ph.D., Cindy Berlinicke, Ph.D., and John Fuller, Ph.D., identified several compounds that appeared to stop the death of retinal ganglion cells (RGCs), the neurons in the back of the eye that, when damaged in glaucoma, lead to vision loss and blindness. Jim Inglese, Ph.D., an expert in cell signaling and assay technologies who directs NCATS’ Assay Development and Screening Technology Laboratory, led the NCATS part of the glaucoma team. Together, the investigators adapted an assay, or test, developed at Hopkins to screen compounds on a much larger scale, including specialized "kinase inhibitor" compounds from GlaxoSmithKline that Inglese had studied extensively. Using these large compound collections and the improved assay, the Hopkins-NCATS team identified many new compounds that showed promising activity in preventing RGC death. But with this success came the next translational roadblock: the need to determine how the compounds worked to prevent cell death. The image on the left shows the optic disc from a normal eye. The image on the right shows the disc from an eye in which the optic nerve has been damaged by glaucoma. Overcoming this roadblock required specialized expertise, so the team followed the NCATS playbook and asked another scientist to join them: Scott Martin, Ph.D., who leads NCATS’ RNA interference (RNAi) initiative. Scientists use RNAi to investigate the function of genes, reveal networks of genes involved in health and disease, and identify molecular targets for intervention. Using an RNAi technique involving molecules called small interfering RNAs (siRNAs), Martin and his colleagues can turn down every gene in the human genome one by one, gaining unprecedented insights into the full collection of genes involved in a disease. In this case, Martin and Welsbie used RNAi to identify the target of the compounds Inglese and Zack had identified. To do so, the team had to employ yet another new technology: RNAi screening in “primary” RGC cells. These cells are taken directly from a retina rather than artificial cell lines cells created in a lab. "Researchers typically use standard cell lines in RNAi studies, but they aren’t the most accurate models of disease," explained Welsbie, first author on the PNAS paper. Researchers have used primary cultures of mouse RGCs for a wide variety of studies, but scientists had never used primary RGCs successfully in an RNAi screen. Working together, the Hopkins-NCATS team successfully delivered the siRNAs to RGCs by attaching them to magnetic nanoparticles and using a magnet to draw the nanoparticles into the cells. The team must conduct further studies using this new method to determine if it will work on other primary cell types. If successful, this advance could help meet the translational need for more accurate cellular models of human disease. Martin’s team used almost 2,000 siRNAs to "knock down" every gene in the RGCs that works as a kinase. Kinases are major controllers of the many biochemical pathways involved in health and disease, and blocking them one by one can identify kinases that control a certain action, such as preventing diseased RGCs from dying. Knocking down most of the kinase genes had no effect, but one, dual leucine zipper kinase (DLK), had a remarkable effect. Blocking the function of the DLK gene in cell and mouse models of optic nerve injury dramatically increased the survival of RGCs. This finding gave the Hopkins-NCATS team critical information: DLK was the target they needed to block to prevent RGC death. So they rushed back to the many compounds they had identified using the assay to find compounds that inhibited DLK. The team searched their screening results and information in the NCATS Pharmaceutical Collection, a database of all approved drugs, to identify a compound that prevented RGC death in their assay and was also known to block DLK. They were excited to find that the compound tozasertib had both needed properties, and they predicted that this compound would have the same effect as DLK knockdown, increasing survival of RGCs. The final step of the translational process was to test this prediction. As they had hoped, the Hopkins-NCATS team found that tozasertib effectively prevented RGC death in rodent models of not only glaucoma but also traumatic optic neuropathy, a condition in which an injury to the optic nerve results in vision loss. Although hurdles remain before this approach can be used in the clinic, these studies offer a crucial new target for the treatment of widespread diseases that cause blindness. Tozasertib is not a practical treatment candidate for glaucoma patients because it was developed for short-term use to treat cancer and has effects on other kinases that would lead to side effects with long-term use. The Hopkins scientists now are testing additional compounds in hopes of finding one that can specifically target DLK without the side effects of tozasertib. In a related collaboration, funded by the Foundation Fighting Blindness, the Hopkins-NCATS team is working to identify promising drug leads for other retinal degenerative diseases based on the therapeutic strategy developed in this collaboration. Zack noted that working with Inglese, Martin and their colleagues enabled his scientists to serve as integral partners in the research process. "What made our collaboration a bit different was that we didn’t just hand off our biological assay for another team to screen," Zack said. "Rather, our researchers were intimately involved in the small molecule and RNAi screens. It allowed us to learn from NCATS researchers and vice versa, with each of us gaining some expertise in the process, and the complementarity of the collaboration led to a more successful outcome." "This remarkable story illustrates NCATS principles and impact beautifully," said NCATS Director Christopher P. Austin, M.D. "The collaborative research team came together to solve a problem neither could solve alone. They developed multiple new methods to overcome sequential translational roadblocks, demonstrated their effectiveness in glaucoma and disseminated those advances in publications. These innovative approaches now promise to benefit many other researchers seeking to identify molecular targets and potential therapeutic strategies in a wide spectrum of diseases." Winners will be invited to speak at the 2013 DREAM conference held November 8–12 in Toronto, Canada. Posted August 2013 | ||||||||
| 555 | IRB Reliance: A New Model for Accelerating Translational Science | Clinical research studies and trials are important steps in successfully translating knowledge gained in the laboratory into interventions that improve human health. They enable researchers to understand the mechanisms underlying disease, improve disease diagnosis, and test the safety and efficacy of potential new drugs and interventions in patients and healthy volunteers. However, launching human studies can be complicated and sometimes takes many months. A major contributor to the time delays is the complex research protocol review and approval process. For each new study or trial that a scientist proposes, an institutional review board (IRB) — made up of scientific, nonscientific and community members — must review and approve the study. IRB oversight ensures that the investigators have safeguards in place to protect human participants from harm, and that the research is conducted safely and in the most ethical way. The IRB review process can be especially cumbersome for researchers and IRB staff conducting multisite research (i.e., conducted at several locations). Yet, multisite studies are critical to translational research because they provide researchers with access to larger numbers of participants, which can enhance the validity of results. Multisite studies are designed to foster collaboration among investigators, which can improve problem-solving and idea-generation. Traditionally, each site’s IRB separately reviews a study or trial protocol. If one of the IRBs requests changes to the protocol, each of the other IRBs must also review and approve those changes, a process that can be time-consuming and inefficient. Researchers also must comply with the rules and processes created by each IRB, which adds to the challenges. This complicated review process may discourage some researchers from initiating important studies. Addressing these challenges is a key part of NCATS’ mission to make translational research more efficient. NCATS’ Clinical and Translational Science Awards (CTSA) program, which supports more than 60 research institutions nationwide, is designed to encourage collaboration across institutions and to remove or minimize common translational barriers, such as those involved in IRB oversight. Improving this process could ease burdens on investigators, encourage them to conduct more multisite studies, and help them obtain trial results faster to speed development of new preventions, diagnostics and treatments for patients. Several CTSA grantees have achieved significant progress in this area using a concept called IRB reliance. In the IRB reliance model, institutions develop networks in which each of the IRBs in a multisite study agrees to rely on a single involved IRB to review, approve and monitor the study. That IRB is designated as the “IRB of Record,” and it takes on most or all of the human subjects protection responsibilities for the study. The other IRBs agree to rely on the decision-making of the IRB of Record. A critical part of any reliance system is a shared infrastructure that enables all participating organizations in the reliance agreement to submit and access materials on studies and trials in which they are participating. Within the CTSA program, institutions participating in IRB reliance networks have shown that efficient and centralized oversight can accelerate translational science. IRB Reliance in Action Among the many casualties from the April 2013 Boston Marathon bombing were dozens of patients who sustained blast-related ear injuries. In the days and weeks following the tragedy, Boston-area clinicians found themselves treating large numbers of patients with blast traumas to the ear, injuries rarely seen outside combat zones. Doctors at Massachusetts Eye and Ear Infirmary (Mass. Eye and Ear), affiliated with Harvard Medical School, realized that if they could learn more about the nature of blast-related ear injuries by studying bombing victims, they could provide more effective treatments and better prepare the medical community to respond to such tragedies. The doctors acted quickly to create a team with four other Harvard-affiliated hospitals — plus three other sites — to design a high-quality multisite study. They also needed rapid IRB approval due to the unusual opportunity to study a large number of ear injuries from the same blast, and to observe patients as they healed. Fortunately, with CTSA program support, Harvard already had an IRB reliance network in place via Harvard Catalyst, (the Harvard CTSA). The lead investigators at the seven sites involved in the study requested their IRBs to rely on Mass. Eye and Ear as the IRB of Record for this study. Within days, the participating institutions agreed. The Mass. Eye and Ear IRB immediately reviewed and approved the study, and patients began enrolling at all sites soon thereafter. Study investigators then began collecting data on the characteristics of blast trauma ear injuries, how they heal, how they respond to treatments such as steroids, and how hearing loss persists or improves over time. This data collection and analysis is ongoing with preliminary results expected to be published this summer. “Launching the study would have been challenging, if not impossible, without the IRB reliance agreements,” said Alicia Quesnel, an otolaryngologist at Mass. Eye and Ear and lead researcher of the study. “The streamlined IRB process allowed us to avoid a great deal of redundancy and overlap so we could focus our efforts on enrollment, data collection and analysis.” Since 2010, Harvard University and its affiliated academic healthcare centers have used the Harvard Catalyst IRB reliance agreement to manage protocols for more than 1,100 multisite studies. Currently, the network includes more than 20 institutions affiliated with Harvard, as well as other academic health centers, some but not all CTSA program-affiliated, in the Boston area. Soon the agreement will include institutions in other New England states. The Harvard Catalyst regulatory team is collecting data to measure the network’s progress; so far, the numbers paint a promising picture. The network IRBs seem to embrace the reliance process: Of the more than 1,100 requests, network IRBs agreed to rely on another IRB for more than 85 percent of the requested studies. Reliance Opens Doors to New Opportunities Other CTSA institutions across the country have created their own local reliance agreements in recent years. In Ohio, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland Clinic, MetroHealth, the University of Cincinnati, Cincinnati Children’s Hospital Medical Center, The Ohio State University and Nationwide Children’s Hospital created — with support from their related CTSA grants — an IRB reliance agreement network comprised of eight affiliated sites. The network includes institutions within the affiliated health systems that do not have direct CTSA program support, thus facilitating collaborative studies at many institutions and enabling the enrollment of more potential participants. Although the Ohio reliance network is relatively new, 20 multisite protocols have used a single IRB of Record between mid-2012 and the end of 2013. Before the Ohio group built a centralized online submission system called HUB to store and access study information, approval took an average of 25 days; now, that average is eight days. “The system is making studies possible that would not have been otherwise,” said Philip Cola, vice president, Research and Technology at University Hospitals Case Medical Center and director, Regulatory Knowledge and Support Core of the CWRU CTSA. For example, researchers from MetroHealth in Cleveland, a county-operated health care system with a small population base, were able to launch several maternal-fetal health studies under a reliance agreement with the University Hospitals system. By conducting the studies at two sites, the investigators were able to boost the numbers of participants so that the study could be completed more quickly. These agreements also can provide researchers with access to technology that typically is not available to them. When another group of MetroHealth researchers wanted to initiate imaging studies that included functional electronic stimulation, a technology not available at MetroHealth, they collaborated with a reliance network institution with the required technology. This access enabled the investigators to conduct a study more easily than prior to the development of the reliance network. A Nationwide Movement In 2006, several California institutions supported by CTSA grants began building their own IRB reliance network. The current agreement includes 10 University of California campuses, including five with CTSA grants and the Lawrence Berkeley National Laboratory. The network originally covered low-risk studies only, and 600 such multisite protocols have used a single IRB of Record. The IRB reliance network recently expanded to include higher risk interventional research in which participants receive experimental therapies or treatments. These studies require closer IRB oversight, which is streamlined by a single, dedicated IRB of Record. The Harvard, Ohio and California reliance network examples reflect a CTSA program-led approach to more efficient and potentially more careful oversight of research with human participants. CTSA program-supported institutions in states such as Wisconsin, Minnesota, Texas and Oregon also have established IRB reliance agreement networks. The leaders in these regional networks are expanding their participating institutions and sharing their experience within and outside of the CTSA consortium. Innovation in IRB practice exemplifies the NCATS “3Ds,” the development, demonstration and dissemination of transformational improvements in the efficiency and effectiveness of translational science. “These regional IRB reliance networks are addressing a major roadblock to efficient clinical studies,” said NCATS Director Christopher P. Austin, M.D. “The progress developed across CTSA institutions in IRB reliance is now driving further innovation and participation across the consortium. IRB reliance is just one of the many NCATS-supported innovations that is making the Center’s mission — to speed translation and improve human health — a reality.” Posted May 2014 | ||||||||
| 554 | Improved Disease Model Leads to Potential Therapy for Rare Disorder | Too many potential drugs fail in human clinical trials despite early promise in animal or cell models of disease. Because these models often do not adequately represent human biology, they don't always accurately reflect how patients will react to an experimental compound. A major area of emphasis at NCATS is the development of model systems for drug testing that more closely resemble human physiology. Such advances can save enormous amounts of time and expense by preventing unsuitable drugs from making their way into human clinical trials. As an example of this approach, researchers from NCATS and the National Human Genome Research Institute (NHGRI) recently found a way around the roadblock of inadequate models for compound testing. Working collaboratively, these scientists developed a potential treatment for patients with Gaucher disease, a rare, inherited condition marked by enlargement of the liver and spleen, anemia, nose bleeds, easy bruising and bleeding, bone problems, and occasionally neurological problems. The team’s findings were published in the June 11, 2014, issue of Science Translational Medicine. Gaucher disease is caused by mutations in the gene that codes for an enzyme, glucocerebrosidase (GCase), which helps cells break down waste. In patients with the disorder, defective GCase impairs the functioning of cells called macrophages. Normally, macrophages travel around the body, engulfing dead cells or pathogens such as bacteria. Once inside the macrophage, this cellular debris is shuttled into compartments called lysosomes, where GCase helps degrade it so it can be cleared from the body. In Gaucher disease, however, GCase is misshaped and disposed of before it can get to the lysosomes. As a result, undigested lipids (fatty substances) from dead cells accumulate in the lysosomes of cells in organs such as the liver, spleen, bone marrow and brain. An intervention commonly used for Gaucher disease is an intravenous infusion that replaces defective GCase with a normal form of the enzyme. However, the treatment costs $200,000 to $400,000 per patient per year, and these individuals must receive the therapy twice a month, often for the rest of their lives. Ellen Sidransky, M.D., senior investigator in the Medical Genetics Branch of NHGRI and senior author of the paper, has spent the past 25 years studying the biology of Gaucher disease in both patients and animals. "Enzyme replacement has changed the quality of life for many patients," Sidransky said. "Our goal is to find a cheaper and more effective way to treat this disorder." A Collaboration Is Born Several years ago, Sidransky suspected that a potential therapy could be a small molecule that would attach to GCase, helping correct how the mutant protein is folded and facilitating its transport toward the lysosome to digest lipid waste. Such compounds are called "chemical chaperones." However, Sidransky needed a way to find the right chaperone. In 2005, she heard about the large-scale molecular screening efforts at what is now the NCATS Chemical Genomics Center (NCGC), part of the NIH Common Fund’s Molecular Libraries Program (MLP). Through MLP, NCATS researchers provide large-scale screening capacity and other resources necessary to identify small molecules that can help scientists study the functions of genes, cells and biochemical pathways. Sidransky approached NCGC experts with her problem, which became one of the first rare disease projects approved for MLP support. The research team performed a series of screens of NCGC's small molecule library, yielding several promising molecules that enhanced both normal and defective GCase function. When the group tested the top chaperone candidates in skin cells from Gaucher patients, they found that the compounds increased the amount of GCase in the lysosomes — another sign of therapeutic potential. The molecules were particularly promising because they were the first "non-inhibitory" chaperones identified. Up until that point, the group had found only compounds that were inhibitory: at low doses, they acted as chaperones for GCase, but at higher doses, they could inactivate the enzyme, making proper dosing a tricky balancing act. The non-inhibitory chaperones, on the other hand, presented none of these problems. With these more promising chaperones, it became clear that Gaucher skin cells were imperfect models in which to test the compounds. The skin cells do not accumulate cellular waste like macrophages, the cells primarily affected by the condition. "We wanted to prove that not only does the enzyme function improve, but that it actually degrades the build-up in the lysosome, because that’s what causes the disease process," Sidransky explained. "But we were stuck because we didn’t have a good model for showing that." Building a Better Model Recognizing the limitations of skin cells, the NCATS-NHGRI team worked to develop a better model. They wanted to use macrophages created from the blood of Gaucher patients to test the chaperone molecules. But macrophages, especially diseased ones, are notoriously hard to keep alive in a laboratory environment. To create enough of the cells for the large-scale screening studies, the researchers would need to continually draw large amounts of blood from Gaucher patients, a process that was both impractical and burdensome. NHGRI's Elma Aflaki, Ph.D., first author on the paper, found a way around this obstacle by turning patient-derived adult stem cells into macrophages. The stem cells provided the team with a continuous supply from which to create macrophages, eliminating the need to draw blood from patients. The patient-derived macrophages showed the characteristic low GCase activity seen in patients and — unlike the skin cells — exhibited increased storage of cellular waste in their lysosomes. One of the chemical chaperones identified from the screens reversed these disease features, returning the macrophages to normal functioning. The NCATS-NHGRI team now is working to optimize the molecule for testing in Gaucher patients. A Potential Treatment for Other Diseases The team's work not only represents a major advance in the understanding and treatment of Gaucher disease, but it provides a model for scientists to study and explore in other conditions — a major part of the NCATS mission. "We can use what we’ve learned about Gaucher disease to understand neurological disorders that may share underlying molecular defects, and we can tackle them in a similar way," said Juan Marugan, Ph.D., an NCATS staff scientist who, along with colleagues Wei Zheng, Ph.D., and Noel Southall, Ph.D., has worked with Sidransky and her group on the screening efforts. For example, Sidransky's group has shown that defective GCase is involved in some forms of Parkinson’s disease and related disorders. Parkinson's is a brain disease marked by shaking (tremors) and problems with walking, movement and coordination. Chaperones targeting GCase also could represent potential therapies for this condition. "What we're learning about this rare disease may revolutionize how we approach common disorders like Parkinson's disease and similar conditions," Sidransky said. "For 25 years, I’ve evaluated and worked with these patients. My hope has always been to come full circle with this research, to develop a treatment to bring back to them." With these advances, she and her team are on their way. Posted August 2014 | ||||||||
| 553 | Work with Matrix Screening | NCATS’ combination screening platform experts regularly collaborate with basic researchers and clinical investigators inside and outside the National Institutes of Health on an as-needed basis. The NCATS team currently is working with investigators at the National Cancer Institute to screen for novel therapies targeting multiple cancer subtypes. View these projects. For more information about working with the matrix screening team at NCATS, contact Jennifer Kouznetsova. | ||||||||
| 552 | Five CTSAs Enable NIH-Funded Research on Innovative Allergy Therapy | Peanuts are one of the most common and deadly food allergies, affecting about three in every 500 people across the nation and causing more than half of all deaths from food-related allergic reactions. Finding a new way to treat and possibly prevent the severest of these reactions — and those related to a number of other common foods — could improve the lives of millions. Scientists have discovered a new way of treating food allergy by placing a small amount of the allergen in liquid form under the tongue. Already widely used and approved in Europe to treat environmental allergies, this method, called sublingual immunotherapy, shows real potential for therapeutic development in the United States. But much work remains before that goal can be achieved, including testing the therapy in people. A record of successful clinical trials makes innovative treatment methods like this one more attractive to pharmaceutical companies, which can develop the therapy into a product for delivery to patients. By sharing part of the risk involved in developing and testing new interventions, especially those to treat life-threatening conditions, NCATS aims to "de-risk" innovative approaches and methods, enabling more efficient translation of basic scientific knowledge into useful treatments. In the case of peanut allergy, a consortium of scientists at five institutions that receive NIH funding — including through NCATS' Clinical and Translational Science Awards (CTSA) program — took up the challenge of finding a viable treatment approach. Led by Hugh A. Sampson, M.D., director of the Institutes for Translational Sciences at Mount Sinai Hospital's Icahn School of Medicine in New York City, the consortium is working with CTSA program experts in multisite clinical trials to build evidence for sublingual immunotherapy as an effective and much needed treatment. Food allergies can be dangerous and sometimes lead to death. Even accidental exposure to tiny trace amounts of peanut allergen may cause severe reactions. Of the more than 3 million Americans with peanut or tree nut allergies, only about 20 percent will "outgrow" them and spontaneously stop reacting. Because no treatment is available, Sampson explained, "All we can do is tell them to avoid exposure to foods that trigger the reaction and treat any resulting symptoms." Collaborations to Improve Translational Research For nearly a decade, a group of food allergy experts supported by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) has worked to make life safer for people who suffer from food allergies. Known as the Consortium of Food Allergy Research (CoFAR), the group uses NCATS-supported CTSA program resources to conduct clinical trials. "The CTSA program supports a collaborative interaction that makes studies of this kind possible," said Marshall Plaut, M.D., CoFAR scientific and medical officer and chief of NIAID’s Food Allergy, Atopic Dermatitis and Allergic Mechanisms Section. "The dedicated clinical resources provided by the CTSA sites make it feasible for studies like ours to advance, reducing the difficulties and delays common to multisite trials." The CTSAs also accelerated the research by speeding institutional review board approval, according to David M. Fleischer, M.D., co-leader of the peanut allergy study and associate professor in the Department of Pediatrics at National Jewish Health, a member of the University of Colorado Denver CTSA. "They helped us with the budget and with the protocol submission," he said. Hugh Sampson, M.D. (left), dean for translational biomedical research and the Kurt Hirschhorn Professor of Pediatrics at Mount Sinai School of Medicine, discusses the results of an experiment investigating the cellular mechanisms of peanut allergy with Steven Woo (center), a student, and Wayne Shreffler, M.D., Ph.D. (right), former assistant professor of pediatrics at Mount Sinai School of Medicine. (Matthew Septimus Photo) CoFAR’s work is a textbook example of how CTSA-provided expertise helps investigators conduct complex, multisite clinical trials. To determine if a therapy is effective, all sites must carry out the study protocol to the letter. That requires each site to have a well-trained staff of research coordinators, nurses and — in a food allergy trial — dietitians to direct food preparation. Considering the real potential for a severe, even deadly reaction to the peanut allergen, the research staff also must understand patients’ needs and be prepared for emergency intervention. Such research, in other words, is time and labor intensive, and the staff must be highly skilled. The food allergen is taken every day, so the risk is always present. "In this trial, the CTSAs provided nursing staff, food preparation, equipment and medications, across all sites," Sampson said. To help overcome the obstacles often encountered in translational research, about 60 CTSA-funded medical research institutions across the country work together to address translational science problems that no one organization can solve alone. In addition to Mount Sinai Hospital and National Jewish Health, three other CTSA-funded sites participated in this trial: Johns Hopkins Institute for Clinical and Translational Research, Baltimore; the Translational Research Institute at the University of Arkansas for Medical Sciences, Little Rock; and the North Carolina Translational & Clinical Sciences Institute at the University of North Carolina at Chapel Hill. Testing a New Treatment for Peanut Allergy CoFAR broke new ground with its publication of the first multicenter, randomized clinical test of sublingual immunotherapy for peanut allergy in the Journal of Allergy and Clinical Immunology in January 2013. The consortium also has studied oral immunotherapy — in which patients swallow small quantities of the food that causes an allergic response — as a treatment for food allergies. "The sublingual therapy has fewer side effects," Fleischer explained. "It uses a much smaller dose, so it is safer for peanut allergy. What we don’t know is if sublingual immunotherapy will be as effective." The researchers studied sublingual therapy in 40 people with peanut allergies, divided randomly into two groups. One group of participants received tiny amounts of diluted peanut protein daily, placed under the tongue, and the other group received a placebo. After 44 weeks, 14 of 20 of the people in the group receiving the peanut preparation could tolerate more than 10 times as much peanut powder as they could at the beginning of the study. In other words, many became partially desensitized to peanuts, although this does not necessarily mean they can safely eat them. Even though the results are promising, the amounts of peanut that the subjects can eat currently may not fully protect them from allergic reactions. Further results will determine whether longer duration of therapy will fully desensitize. "Parents of a child with a peanut allergy — or any food allergy — may be happy just to have the child desensitized so they don’t have to worry about accidental exposure," Fleischer explained. Because avoiding trace amounts of peanuts is quite difficult, even a small level of desensitization could make life much easier for those who do not outgrow the allergy. Sampson added that CoFAR members explore all aspects of food allergy. The research team continues to collect data from this trial and is recruiting participants for two new trials that will test other therapies. He is excited about the results of the trial so far. "We think this technique can be applied in the United States to other food allergies," Sampson said. "The CTSA provided clinical trial expertise and resources have been critical to our ability to speed this work and get these trials under way, for the benefit of patients." November 2016 Update: Promising Results for New Peanut Allergy Therapy In October 2016, CoFAR members published one-year outcomes from an ongoing clinical trial testing a new peanut allergy treatment called epicutaneous immunotherapy (EPIT). The therapy is delivered via a wearable patch that transfers small amounts of peanut protein through the skin. The patch shows promise for treating children and young adults with peanut allergy, with greater benefits for younger children. EPIT was shown to be safe and well tolerated, and nearly all participants used the skin patch daily as directed. “The high adherence to the daily peanut patch regimen suggests that the patch is easy to use, convenient and safe,” Plaut said. “The results of this study support further investigation of epicutaneous immunotherapy as a novel approach for peanut allergy treatment.” The CoFAR study team continues to assess the long-term safety and effectiveness of EPIT. The one-year outcomes were published online on Oct. 26, 2016, in the Journal of Allergy and Clinical Immunology. Posted October 2013 |
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