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| 617 | Tox21 Collaboration Generates an Innovative Platform for Testing Individual Differences in Chemical Sensitivity | What if we could predict whether an individual will have an adverse reaction to everyday chemicals, such as those in laundry detergent or perfume? Or whether a particular chemical factory worker will fall ill upon exposure to a particular substance? With the publication of a study from a team of researchers that included NCATS experts, science is one step closer to such a scenario. More than 80,000 chemical compounds are registered for use in the U.S., and for the vast majority of them, there has been no toxicity testing in humans to inform us about their effects on health. Just as genetic differences make each of us more or less susceptible to developing conditions such as heart disease, these differences also could determine how sensitive we are to chemicals in the environment. To establish safe levels of chemicals for human use, regulatory officials traditionally have used animal toxicology data to predict human responses to chemicals. This imperfect practice highlights a critical translational science and public health problem: until now, there has been no way to accurately measure human differences in sensitivity to the chemicals in our environment. A new study, published in the Jan. 13, 2015, issue of Environmental Health Perspectives, introduces a new way around this obstacle, using NCATS’ robotic screening capabilities to test the cells of more than 1,000 individuals with different genetic backgrounds for sensitivity to 179 chemicals. “To fully achieve the promise of precision medicine, we will not only have to understand the extent and genetic basis for human variation in response to therapeutics, but also for sensitivity to chemical toxicity and adverse drug reactions,” said John R. Bucher, Ph.D., associate director of the National Toxicology Program at the National Institute of Environmental Health Sciences (NIEHS), one of the collaborating institutions in the study. “This work provides a possible approach using technologies already in hand.” Addressing a Knowledge Gap Several years ago, experts in the Toxicology in the 21st Century (Tox21) program recognized a critical scientific need not yet addressed by the initiative. Tox21 is a collaboration among researchers from NCATS, NIEHS, the Environmental Protection Agency, and the Food and Drug Administration. Tox21 scientists use a robotic system located at NCATS’ laboratories in Rockville, Maryland, to perform automated tests, or assays, which expose cells and proteins to thousands of chemicals in a short time. This process is called high-throughput screening (HTS). Tox21 experts, including Raymond Tice, Ph.D., now retired from NIEHS, knew that the initiative’s approach yielded valuable information about cell functions affected by chemical toxicity. However, the tested cells all came from only a few cell lines, so the test results had few details about the range of sensitivity to a chemical’s toxicity in the human population as well as which genes affect that variability. But the team suspected that adapting the Tox21 HTS platform to test specific chemicals with known toxicity using cells from hundreds or thousands of people could produce that missing information. To get started, the Tox21 team partnered with scientists at the University of North Carolina at Chapel Hill — toxicology researcher Ivan Rusyn, M.D., Ph.D., now at Texas A&M University, and statistician Fred Wright, Ph.D., now at North Carolina State University, both authors on the paper — who had experience with small-scale testing of cells for genetic variations in toxicity. To draw reliable conclusions about how genes affect chemical sensitivity, the group needed cells that represented a large number of genetically diverse people. Luckily, they were able to acquire lymphoblastoid cells, a type of engineered white blood cell, together with related genetic information from 1,086 people from nine ethnic populations as part of the publically funded 1000 Genomes Project. The initiative is an international effort to catalog human genetic variation by sequencing (i.e., determining the sequence of “letters” in a person’s DNA) the genomes of more than 1,000 people. The researchers were ready to test chemicals on these cells grown in culture (also called in vitro) on a large-scale. Making the Most of NCATS’ Robotic Capabilities With help from automation experts in NCATS’ Division of Preclinical Innovation, the Tox21 team tested the toxicity of 179 chemicals using the cells of those 1,086 people and a technique called quantitative HTS. This innovative method, developed at NCATS, enabled the researchers to run each compound through the assay at eight different concentrations. This approach is more likely to capture the full range of responses from the most to the least sensitive individual. The chemicals tested were substances to which people regularly are exposed, including pesticides, industrial chemicals, food additives and drugs. The study, a massive logistical undertaking, was unprecedented in its scope. “It is the largest population-based, in vitro test with the largest number of cell lines ever done,” Rusyn said. The team found that for about half of the chemicals tested, the range of variability among individual responses was larger than previously assumed. When making regulatory decisions about safe levels of chemicals, environmental experts generally assume that reducing exposure by an extra 10-fold is sufficient to protect people who may be more sensitive to the toxic effects of a given chemical. Specifically, exposure is reduced first by a “toxicokinetic” factor of 3.2, which accounts for differences in how a chemical reaches cells in the body, and then by a “toxicodynamic” factor of 3.2, which accounts for differences in biological responses after a chemical interacts with cells in the body. Although some approaches have addressed the first factor, few researchers have evaluated the second factor, and only at a much smaller scale. This larger study’s findings suggest that the standard toxicodynamic factor is generally applicable, but for about half of the chemicals examined, a larger factor — in some cases greater than 10 — may be more appropriate. This result paves the way for a strategy to develop more precise, chemical-specific exposure factors, rather than the currently used “one-size-fits-all” approach. The researchers also examined the relationship between gene variations (polymorphisms) and cells’ sensitivity to toxicity. They discovered sensitivity-related polymorphisms in several genes involved in transporting substances across the cell membrane. The study was the first to highlight the role of this gene family in susceptibility differences for a range of chemicals. It may point to mechanisms by which chemicals affect human health. Disseminating a New Approach to Protecting Public Health Prior to the paper’s publication, the team released portions of the data to the international scientific community in the form of a data challenge called the DREAM Toxicogenetics Challenge. Such a competition harnesses the power of crowdsourcing to invite scientists to use Tox21 data to develop innovative predictive models for chemical toxicity across populations. The results from this paper, as well as from crowdsourced analyses, could help regulators devise a more accurate way of determining safe levels of environmental chemicals. They also may enable the identification of people who are especially sensitive to certain chemicals. “This work personifies the NCATS 3Ds,” said Christopher P. Austin, M.D., NCATS director. “Our team collaboratively developed a new way to address the problem of individual differences in sensitivity to chemicals; through this paper, we demonstrated that our method works, and we disseminated the results so that scientists can generate their own hypotheses and use the techniques in their own toxicological studies. This approach to studying personalized effects of environmental exposures, like that of precision medicine, embodies NCATS’ mission of finding translational solutions to improve human health.” Posted March 2015 | ||||||||
| 616 | Michael J. Fox Foundation Funds Research Project that Leverages NCATS Chemical Screening Approach and Resources | A key NCATS approach to solving translational problems is to focus on improving scientific methods and tools that can speed the translation of laboratory discoveries into new treatments for patients. NCATS scientists demonstrate the potential of new approaches by incorporating them into a broad range of drug discovery and development projects. Ultimately, these new platforms and ideas can have far-reaching effects as NCATS scientists disseminate them to members of the larger scientific community for adoption in their own studies. With support from the Michael J. Fox Foundation for Parkinson's Research (MJFF), James Inglese, Ph.D., director of NCATS' Assay Development and Screening Technology Laboratory, and Richard Youle, Ph.D., of the National Institute of Neurological Disorders and Stroke, are leading a project that showcases how NCATS' chemical screening resources can advance development of potential therapeutics for a broad range of diseases. "This Parkinson's disease research project embodies what the NCATS mission is all about: the use of innovative approaches to enhance our ability to discover and develop therapeutics to better treat patients," Inglese said. Over the past several years, Youle and his colleagues have unraveled a molecular pathway that appears to be involved in Parkinson's disease, a brain disorder marked by shaking (tremors) and problems with walking, movement and coordination. Progressive death of neurons (brain cells) in an area of the brain that controls movement leads to these symptoms. Scientists believe one cause of this neuronal death is dysfunctional mitochondria, which often are referred to as a cell's "powerhouse" because they generate the energy cells need to function. Defective mitochondria leak toxic substances that have the potential to damage or destroy a cell. Normally, a protein called parkin signals the cell to destroy and remove faulty mitochondria, but for patients with Parkinson's, this maintenance mechanism is disrupted. Youle's group suspected that finding a chemical compound that enhances parkin activity could potentially prevent mitochondrial-induced damage and neuronal death. The compound would open a new therapeutic avenue for treating Parkinson's disease. But the team needed a way to screen for such candidate compounds. Enter Inglese's group, which designs and creates assays that can be used to screen chemical libraries for compounds that have therapeutic potential in a specific disease. A postdoctoral researcher from Youle’s team, Sam Hasson, Ph.D., had been studying the parkin pathway and teamed with Inglese to develop an assay using neuron-like cells grown in a lab. Together, the project team integrated a new screening technology developed by Inglese and his team called coincidence reporting, which uses biological tools known as reporter genes. Through a process called genome editing, the researchers insert two reporter genes within the natural DNA sequence of a gene of interest — in this case the gene for parkin — where they produce detectable signals such as light when the gene under study is expressed. In contrast to the traditional practice of using a single reporter gene, the integration of two different reporters within the gene of interest enables scientists conducting a screen to look for two coinciding signals to indicate that the gene of interest has been affected. Using the coincidence reporting method, the team is conducting quantitative high-throughput (large scale) screening, or qHTS, with NCATS' chemical libraries to identify compounds that increase parkin activity. Inglese and colleagues developed qHTS, a method that involves testing compounds at multiple concentrations instead of one. Screening at multiple concentrations increases the probability of finding potential hits. The NCATS libraries include a collection of about: 400,000 small molecules with known biological activities or the potential to affect biological functions, 25,000 chemical compounds derived from natural product extracts, and 2,750 compounds that already have been approved to treat another condition or have been tested in human studies. The MJFF funding supports the team’s efforts to develop assays, complete the screening, analyze the results and perform follow-up studies with the most promising compounds to narrow down a list of a small number of potential therapeutics. Measuring their efficacy in flies and mice will follow. The hope is to test the best candidates for their ability to treat Parkinson's in human patients. Although the MJFF support is specific to potential treatments for Parkinson's disease, the compounds identified could be used to treat a number of rare diseases also marked by mitochondrial dysfunction. "By screening for potential therapeutics targeting a disruption that occurs in a number of conditions in addition to Parkinson's, we may be able to treat many disorders instead of just one," Youle said. What's more, added Inglese, because Parkinson's gives us the opportunity to work on an innovative process, the improved screening and assay methods that will emerge can be used by other scientists to solve many other translational research problems. In this way, "not only do the patient groups benefit, but the broader scientific community also benefits because the improvements we make will be applicable to many more diseases," Inglese said. "Developing methods that benefit many can have effects far beyond those communities." Posted July 2014 | ||||||||
| 615 | Study Demonstrates Success of NCATS’ Rare Diseases Therapeutic Development Programs | Developing new drugs can take years and cost billions of dollars. Because of the time, expense and likelihood that a promising drug will never make it to market, few companies are willing to investigate new drugs to treat diseases that may not be well understood or provide the potential for a good return on investment. The picture can be even more challenging when it comes to developing drugs for rare or neglected diseases, because there are a limited number of patients to study and because a relatively small market exists for rare disease drugs. To counter these systematic challenges in the drug development pipeline, NCATS runs two innovative late-stage preclinical drug development programs, Therapeutics for Rare and Neglected Diseases (TRND) and Bridging Interventional Development Gaps (BrIDGs). TRND and BrIDGs collaborations and resources are helping scientists translate basic research discoveries into treatments for patients more efficiently by providing a new collaborative model of early drug development that “de-risks” projects to make new drugs commercially viable and attractive to outside partners. “There are many roadblocks in the drug development pipeline that prevent promising therapies from making it to people who need them,” said Anton Simeonov, Ph.D., NCATS acting scientific director. “TRND and BrIDGs create solutions to overcome these roadblocks, and not only apply them to particular drug development projects, but also to rigorously assess their effectiveness and disseminate the approaches so that others can use them.” Have TRND and BrIDGs Worked? Andrew Lo, Ph.D., Charles E. and Susan T. Harris Professor of Finance, Massachusetts Institute of Technology (MIT) Sloan School of Management, and Nora Yang, Ph.D., director of portfolio management and strategic operations, NCATS Division of Preclinical Innovation, led a collaborative research team that conducted a financial analysis of 28 TRND and BrIDGs projects related to rare diseases. The study, published Feb. 25, 2015, in Science Translational Medicine, found that the scientific and operational processes utilized in TRND and BrIDGs projects led to reduced cost of developing new drugs, reduced financial risks, and effectively provided a way to develop promising therapeutics to the point where they could be handed off to the private sector for final testing and marketing. “We started the NCATS rare disease therapeutic development program five years ago,” Yang said. “We saw early signs of programmatic success, but we needed an objective measure to quantify its effectiveness. As scientific innovators, we were delighted to be able to work with Professor Lo and his team, who are leaders in financial innovation. We were excited to find that our portfolio yielded even better results than we expected when our TRND-BrIDGs productivity data were analyzed with Professor Lo’s model.” Although the TRND program is only five years old, one-third of the 28 projects included in this analysis already have attracted independent private funding. Seven compounds from the portfolio have been in clinical testing, including one in a Phase II trial for sickle cell disease. The other compounds in clinical testing are for retinitis pigmentosa, Niemann-Pick disease type C1, GNE myopathy (also known as hereditary inclusion body myopathy), chronic lymphocytic leukemia, beta thalassemia and Friedreich’s ataxia. Two more Investigational New Drug (IND) applications have been successfully filed with the U.S. Food and Drug Administration (FDA), and clinical trials are underway for Duchenne muscular dystrophy and retinitis pigmentosa. In another mark of success, two larger biopharmaceutical companies acquired two companies that had collaborated with NCATS. The acquiring companies, Baxter and Shire, experienced one-day stock market gains of $238 million and $423 million, respectively, on the days the sales were announced. Two new startup companies were spun out from two of the portfolio projects to continue commercialization of projects de-risked by NCATS. The NCATS Model TRND and BrIDGs projects’ lower cost and greater success rates were accompanied by longer preclinical development times than the industry average. “This result was not unexpected, because the programs take a methodical, step-by-step ‘sequential approach’ that reduces drug development costs,” Yang said. The sequential approach differs from the industry standard, which undertakes multiple investigations into a new drug simultaneously. This method moves a successful therapeutic more quickly through the pipeline to market, but it can also cost more if a drug fails, because there is more up-front investment. For each project, NCATS and outside investigators form a project team that develops a project timeline and milestones and defines deliverables and go/no-go milestone criteria. If projects meet all of their milestones, there is greater potential for the therapeutic agent to succeed and that private financing can be secured from pharmaceutical companies, biotechnology companies or venture capitalists. When a project does not meet its milestones, it may be closed out. The TRND and BrIDGs model provides a way to help drug developers navigate through the so-called “valley of death,” the time after a therapeutic agent emerges from preclinical research but before it has undergone final testing for use with patients. “We don’t take a product to market, but we can’t ignore marketability,” Yang said. “Whatever project we put public money into, we have to make sure that we build a compelling value proposition so that private investors will carry it forward and get the final medicine to patients.” The study by the MIT-NCATS team concluded that TRND and BrIDGs provide a realistic business model under which a portfolio of rare-disease therapeutics can yield attractive financial returns. Successful demonstration like this can lead to more private-sector funding for rare-disease therapeutic development, generating system-wide impact on translational sciences. The analysis also suggests that this innovation in translational science and operational models can get more treatments to more people more efficiently and that NCATS can successfully catalyze the partnerships needed to advance translational science. “It’s been a pleasure to work with NCATS, and our findings suggest tremendously exciting opportunities to do well by doing good through closer collaboration between the financial industry and the biomedical community,” Lo said. Planning Next Steps TRND and BrIDGs team members, many of whom worked in the pharmaceutical industry before coming to NCATS, will continue efforts to improve these program models as the next group of projects gets underway. “This kind of analysis is critical to helping us determine if we truly are meeting our mission of ‘advancing translational sciences,’” Yang said. “Now that we know our programs have produced better success rates and lower costs, we need to understand the factors in our science and operations that underlie the improvement. Understanding these success factors will be crucial for NCATS, through its preclinical therapeutic development programs, to further increase efficiency, and to articulate our models in sufficient detail that others can adopt them.” “This remarkable collaboration exemplifies a number of NCATS core principles,” said Christopher P. Austin, M.D., NCATS director. “Bringing distinct expertise together — in this case drug development and financial engineering — leads to the greatest advances in science.” More on TRND and BrIDGs TRND and BrIDGs researchers provide in-kind resources and expertise to help collaborators complete the necessary investigation and development studies that the FDA requires. Collaborators include academic institutions, biotechnology companies, NIH intramural laboratories, patient groups and pharmaceutical companies. The drugs currently being developed for rare diseases cover a variety of conditions, including for central nervous system diseases, musculoskeletal diseases, endocrine disorders, cancers and cardiovascular disorders, among others. Five of the current projects involve new uses for existing drugs, 13 for new molecular entities, 8 for large molecules, 1 for stem cell therapy and 1 for gene vector therapy. Posted February 2015 | ||||||||
| 612 | BrIDGs Expertise | BrIDGs scientists bring decades of experience in industry and academic drug development to each project. Collaborators tap into staff expertise in process chemistry, formulations development, pharmacokinetics and toxicology. These scientific insights are combined with a thorough understanding of regulatory guidelines, which enables the program to provide assistance with establishing and implementing successful product development plans for IND applications. Completed and active projects include small molecules, peptides, gene therapies and recombinant proteins delivered by oral, topical and injectable routes of administration. | ||||||||
| 611 | CTSA Consortium Tackling Clinical Trial Recruitment Roadblocks | Creating safe and effective treatments, diagnostic tools and medical devices that improve human health requires successful testing of those interventions in humans. Researchers nationwide face common barriers in recruiting (or accruing) enough participants for clinical trials. The inability to identify and recruit the right number and type of people to participate often: Makes clinical trials slow and more costly; Limits the validity of trial results and, in turn, researchers’ ability to apply the findings broadly to the general population; and Stops a trial prematurely or prevents it from taking place at all. In fact, a recent analysis of more than 7,500 Phase II and III cancer trials registered on ClinicalTrials.gov between 2005 and 2011 found that 20 percent were never completed. The most common reason: inability to recruit participants. One promising way to identify clinical research participants is to access information contained in electronic health records (EHRs) across the country. This solution is not without problems: For example, in addition to legal limits and privacy concerns, typically, the medical data are not linked across institutions, and EHRs frequently do not “talk” to each other easily because they use different terminology for the same information. CTSA Program Solutions NCATS’ Clinical and Translational Science Awards (CTSA) program supports efforts to solve system-wide translational research problems in part by developing and implementing ways to improve the success of U.S. clinical trials. One initiative, CTSA Accrual to Clinical Trials (CTSA ACT), was launched recently to do just that by developing a nationwide network of sites that share EHR data. Building on existing platforms and operating models to create a “federated” network with common standards, data terminology and shared resources, CTSA ACT investigators are focused on: Data harmonization (using the same term for the same type of data) across EHR platforms; Technical needs assessment and implementation; Regulatory approaches to ensure compliance with protocols for data access and participant contact; and Governance development to establish proper agreements among institutions. “We are approaching the challenge of identifying and enrolling patients by linking EHRs to identify potential participants who meet study criteria,” said Steven E. Reis, M.D., a professor and associate vice chancellor for clinical research at the University of Pittsburgh, and director of the University of Pittsburgh Clinical & Translational Science Institute. He added that the ACT team created standard categories and terminology for demographic and clinical visit data as well as for medications and laboratory results. “Recruiting participants into clinical trials is a critical success factor in our ability to bring more treatments to more patients more quickly,” said Petra Kaufmann, M.D., M.Sc., NCATS Division of Clinical Innovation director. “The CTSA ACT investigators are tackling this challenge using innovative tools not only to find out where potential participants are, but they also are beginning to look at better ways to then connect participants with research opportunities.” Technology Platforms The CTSA ACT technology platform has two major components: Informatics for Integrating Biology and the Bedside (i2b2), a software package that converts raw records into de-identified and searchable participant information stored in a central database. Shared Health Research Informatics Network (SHRINE), a search engine for i2b2. With appropriate agreements in place, an ACT investigator can use SHRINE to search de-identified records using a customized set of participant criteria. SHRINE queries all network institutions and provides an approximate number of participants at each site who meet the criteria. The i2b2/SHRINE technologies are open source (available to anyone) and widely used, for example in NIH-funded studies at Harvard Catalyst, the university’s Clinical and Translational Science Institute. This enabled the ACT team to get the first sites up and running quickly. Because these technologies are just two of the solutions in use across CTSA hubs, one objective is to identify and integrate hubs that do not use i2b2 into the ACT network. So far, ACT researchers have tested the technology at 13 CTSA hubs. All of these sites have obtained approval from their IRBs, and, to date, eight additional CTSA hubs have been selected for inclusion in the project moving forward. Participant Screening and Recruitment CTSA ACT will enable a qualified investigator to quickly determine, approximately how many participants might be available for a study and where they are located, all in a de-identified way. Once a scientist knows how many potential participants meet the criteria for a trial, the next step is to find out who they are and to contact them to discuss whether they would consent to participating in the trial and for additional screening. Any personally identifiable information must be shared in a legal and ethical manner; therefore, CTSA ACT will implement an approach that has overcome these challenges. “We must protect privacy while advancing research, and we are actively discussing those issues,” said Gary S. Firestein, M.D., professor and dean and associate vice chancellor of translational medicine at UC San Diego. “We are sensitive to the fact that patients may be uncomfortable with the notion of someone in a different health system looking through their records. That’s why this work is done with de-identified data.” One solution is for each site to have a designated local investigator who will serve as an “honest broker” or “data concierge.” This individual sorts through patient records to identify participants in that region and to figure out the right way to contact them. After a contact request is approved, normal IRB oversight and the local investigator ensure that participant privacy is protected. CTSA ACT leaders also are working to ensure their efforts complement a similar Patient-Centered Outcomes Research Institute (PCORI) nationwide network under development, called PCORnet. “As CTSA ACT and PCORnet take shape, we are aiming for synergy,” explained Robert D. Toto, M.D., professor and associate dean for translational science at the University of Texas Southwestern. “The goal is to ensure that we develop methodologies in concert with PCORI to make the ACT and PCORnet data interoperable for future initiatives.” Existing Resource Collaborations While unique in the number of institutions that will be joined in a cooperative network, CTSA ACT is building on a strong foundation of existing CTSA resources and models. One CTSA-supported federated network also using the i2b2/SHRINE technology is the University of California Research eXchange (UC ReX), a secure, Web-based system that enables UC investigators to identify potential study participants using data from patient care activities at the five UC medical campuses: Davis, Irvine, Los Angeles, San Diego and San Francisco. CTSA investigators are integrating UC ReX into CTSA ACT, and many of the best practices established in UC ReX’s development will inform ACT’s continued growth. “Other CTSAs have developed informatics platforms and established participating sites, so we can build on that foundation,” Firestein said. The ACT team also is tapping into the knowledge of CSTA-supported investigators who have developed a variety of patient registries aimed at improving trial accrual; some registries have recruited more than 10,000 participants. Frontiers: The Heartland Institute for Clinical and Translational Research is another CTSA hub with an established federated network, called HERON (Healthcare Enterprise Repository for Ontological Narration). Using the i2b2 technology as the foundation, HERON enables access to de-identified EHRs by faculty across the campuses in the University of Kansas system. The Frontiers network includes partners at the Kansas City University of Medicine and Biosciences, 10 hospitals and health systems in Kansas and Missouri, and 14 community partners in both states. HERON has a patient registry with more than 30,000 participants. One approach used by Frontiers is to ask patients during office visits if they are interested in clinical research; patients can sign a brief consent form that authorizes research-related contact and inclusion of their medical information in a registry. Another is setting up a Web-based registry, such as the CTSA-supported ResearchMatch, for interested patients and healthy volunteers. Both UC ReX and HERON are in early development, but investigators are collecting and analyzing data to determine the effectiveness of these networks in improving trial accrual. Examples from both suggest that using technology to streamline and improve the accrual process works. UC ReX enabled UC’s participation in a large, multisite comparative-effectiveness study — “Comparing Options for Management: Patient-Centered Results for Uterine Fibroids,” funded by PCORI and the Agency for Healthcare Research and Quality — by demonstrating in an efficient way that UC had enough qualified participants. Without UC ReX, the process had been lengthy and often inaccurate. With similar goals, Frontiers has made steadily increasing use of HERON, launched in 2012; in its first two years, researchers used the technology to enroll 150 participants in clinical trials. This number is expected to grow as investigators become used to the new process and the benefits it can provide. Expanding CTSA Support In addition to and building on these ongoing efforts, NCATS plans to fund two Recruitment Innovation Centers (RICs) in fiscal year 2016 through the CTSA program. The program will focus on improving accrual into multisite clinical trials through innovative informatics and technology-driven approaches as well as developing ethics and policy frameworks and improved ways to connect participants to trials. “The RICs will support new ways to assess the feasibility of recruitment and selection of research sites for multisite studies while implementing strong privacy safeguards and sufficient permissions for data access,” Kaufmann said. “They will also help us find better ways to connect participants with research opportunities and collectively share our goal to enable evidence-based understanding of what works best in trial participant recruitment.” Posted February 2015 | ||||||||
| 610 | About BrIDGs | The Bridging Interventional Development Gaps (BrIDGs) program enables research collaborations to advance candidate therapeutics for both common and rare diseases into clinical testing. Investigators do not receive grant funds through this program. Instead, selected researchers partner with NCATS experts to generate preclinical data and clinical-grade material through government contracts for use in Investigational New Drug (IND) applications to a regulatory authority such as the Food and Drug Administration (FDA). In general, BrIDGs provides synthesis, formulation, pharmacokinetic and toxicology expertise and resources to its collaborators. NIH contractors conduct preclinical studies under the direction of NCATS staff. NCATS, along with any co-funding NIH Institutes and Centers, supports contract costs. The decision to collaborate on a proposed project is based on an internal assessment of scientific merit, programmatic fit and the availability of NIH funds. Find out how to submit a proposal to BrIDGs. As of fall 2015, BrIDGs has generated data to support 18 investigator-initiated INDs that have been cleared by the FDA and one clinical trial application cleared by Health Canada. A total of 14 projects have been evaluated in clinical trials. Five BrIDGs-supported agents have been evaluated in Phase II human clinical trials, in which researchers give an experimental therapy to a group of patients to evaluate the effectiveness and safety of a treatment. Third-party organizations have licensed or invested in 10 agents during or after their development by BrIDGs. Learn more about BrIDGs projects. | ||||||||
| 609 | Searching Saliva for Signs of Disease | The recent and premature death of ESPN anchor Stuart Scott at just 49 years old focused the media spotlight on a lesser-known form of cancer with a deadly track record: Gastric (stomach) cancer kills more than 800,000 people worldwide each year. Unfortunately, most patients do not notice symptoms until the disease has advanced too far for current treatments to be effective. What if clinicians could diagnose and treat a wide range of diseases, including stomach cancer, just by understanding the “conversations” between cells and then eavesdropping on the human body? Extracellular RNA (exRNA) — RNA that is outside the wall of a cell — could enable just that. Scientists have discovered that exRNAs help cells talk to each other. But before exRNA can fulfill its potential, researchers need to know more about how it works in the body. RNA helps translate genes into the proteins that organisms need to function. Recent research has shown that cells can release RNAs in the form of exRNAs to travel via fluids such as blood and saliva. Acting as a signaling molecule, exRNAs communicate with other cells and carry information from cell to cell throughout the body. Sampling and sequencing these exRNAs may provide a snapshot of what is going on in the body at that time and provide scientists with insights into disease. Through the NIH Common Fund’s Extracellular RNA Communication program, NCATS and other NIH Institutes and Centers support research on how exRNA could be used to improve diagnosis and treatment for diseases such as cancer, bone marrow disorders, heart disease, Alzheimer’s disease and multiple sclerosis. This trans-NIH effort includes leadership and participation by NCATS, the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute on Drug Abuse. Specifically, NCATS oversees the part of the program that uses exRNA for biomarker and therapy development. Potential Biomarkers for Cancer Researchers at the University of California, Los Angeles (UCLA) are exploring how exRNA in saliva could be used as biomarkers to detect gastric cancer. The team announced findings published in the January 2015 issue of Clinical Chemistry. While previous studies described only some of the exRNAs found in saliva, this study was the first to catalog all small noncoding exRNAs in saliva. The UCLA team found that saliva contains many of the same molecules found in blood. The molecular profiles of different people varied in the same way that molecular profiles of blood do. This finding suggests that saliva represents a person’s health just as well as blood can. The researchers are using these findings to develop a new, noninvasive diagnostic test for stomach cancer. “Had it not been for the NIH Common Fund initiative, we would not have been able to see what we are seeing now,” said David T.W. Wong, D.M.D., D.M.Sc., a senior author of the study and director of the UCLA Center for Oral/Head & Neck Oncology Research. Wong has been studying saliva for more than a decade. Working with the other senior author of the study, RNA bioinformatics expert Xinshu (Grace) Xiao, Ph.D., was key. “One of the benefits of this program is cross-collaboration with a brilliant RNA biologist,” Wong noted. “Dr. Xiao’s expertise enabled us to see the classes of RNA in the saliva. For this, I am scientifically grateful.” Describing the Contents of Saliva Wong and Xiao began with saliva samples from healthy volunteers. They removed the cells from the sample and worked only with the fluid. Using high-throughput RNA sequencing techniques, they analyzed the small noncoding RNA in the saliva. One type of RNA that they found was microRNA (miRNA), which help regulate gene expression inside a cell’s nucleus. The scientists found that miRNAs were abundant in saliva and that they were present at similar levels in different people. They also found that the miRNA profiles of saliva are similar to those of other body fluids. Circular RNAs (circRNAs) were also common in the samples; Wong and Xiao identified more than 400 circRNAs in saliva. Unlike linear RNA, which break down easily, circRNAs are stable. “Circular RNAs in saliva may be protecting other RNA,” Xiao said. They may keep the vulnerable miRNAs from degrading during travel to another part of the body. Other research funded by the same NIH initiative suggests that circRNAs may pick up other types of RNA and carry them around the body to deliver messages, similar to the function of hormones. Of special note, the team also found piwi-interacting RNAs (piRNAs), which are involved in silencing DNA. Until now, scientists commonly found this kind of RNA in stem cells and the cells that become eggs and sperm, but rarely in bodily fluids. Wong and Xiao’s discovery of high levels of piRNA in saliva was unexpected and indicates a need for further scientific exploration. Is the Mouth a Window to the Body? Although Wong and Xiao do not know what biological role the noncoding RNA play in saliva, the results show that this fluid could have huge value as the basis for diagnostic tests because it reflects what is going on in other parts of the body. RNA arrive in the mouth by two routes: (1) from leaking out of blood vessels into the crevices between the teeth and gums and (2) from the salivary glands, which are fed by blood vessels and can actively pull in molecules from the blood. “That information from the bloodstream is downloading into the saliva,” Wong explained. “No part of our body is in isolation,” Wong said. “Our opportunity is to identify how the parts cross-talk.” The information in saliva could provide a snapshot of the biological processes going on throughout the body. That means sequencing the right molecules could tell you whether a person has a disease. “Noninvasive tests are the holy grail of diagnostics,” Wong said. Saliva is a particularly good candidate for diagnostic tests because it is abundant — we make about a liter to a liter and a half every day — and easy to sample. Providing a saliva sample is more pleasant than having blood taken and less embarrassing than providing some of the other fluids used in diagnostic tests. Translating Discovery into Action Wong and Xiao are working to develop a saliva test to detect gastric cancer by collecting saliva samples from 200 people, half with and half without cancer. Now they are sequencing the exRNAs in the samples. When they have found possible cancer markers, they will recruit 1,500 more people to test the markers in a more powerful study. Wong expects to know definitively whether the test works in about four years. “This research not only shows how exRNAs could be useful for detecting stomach cancer, but it opens the door for scientists to use saliva and other biofluids as a way to detect other diseases,” said NCATS Associate Director for Special Initiatives Dan A. Tagle, Ph.D., M.S. “Here at NCATS, we look for truly innovative approaches in what is common across diseases in an effort to accelerate discovery before sharing this information broadly to the scientific community.” Collaboration among exRNA consortia investigators has meant rapid development of new thinking about what exRNAs can do. Not only could this research advance the field of exRNA communication, it also could lead to real applications in the clinic. A more thorough understanding of exRNA could even lead to the development of new devices, such as wearable chips that could detect new diseases and monitor the status of chronic ones. These kinds of ideas, made possible by exRNA, could help change a diagnosis of stomach cancer — and many other cancers and unrelated conditions — from a grim identification of advanced disease to early detection and effective treatment. It could help prevent the untimely deaths of people like Stuart Scott. It could even point the way toward the future of precision medicine. Posted February 2015 | ||||||||
| 608 | BrIDGs Program Goals | The high cost of translating therapeutic discoveries into clinically available agents can deter the development of promising therapies. Researchers may partner with private-sector entities to advance projects with significant commercial potential, but high-risk ideas or therapies for uncommon disorders frequently do not attract investors. When private-sector resources are limited, BrIDGs research and development expertise and services can help researchers bridge the gap between the preclinical and clinical stages of therapeutic development. This support enables continued evaluation of agents that may improve the standard of care for patients with a variety of diseases and disorders. | ||||||||
| 607 | NCATS Repurposing Test Identifies 53 Drugs that May Block Ebola Infection | The world has witnessed an unprecedented outbreak of the Ebola virus in West Africa, and Americans have felt the fear brought on by documented cases of the virus within the United States. Health care workers and researchers have made significant efforts to contain and quell the effects of the virus, which has a 70 percent death rate in some areas, but no approved treatment for Ebola yet exists. The search for effective treatments has lagged because of limited supplies of antibody-based therapies, a lack of clinical trials, and the sheer amount of time needed to develop and deploy treatments such as vaccines. Time- and money-saving efforts become critical in such public health crises, and drug repurposing is a viable option that has great potential. A team of researchers from NCATS and the Icahn School of Medicine at Mount Sinai decided to approach the problem in precisely that way: by screening existing drugs. The study, published in Emerging Microbes and Infections, describes the team’s collaborative efforts to develop a miniaturized assay for high-throughput screening (HTS) to screen for compounds that block the ability of Ebola virus-like particles (VLPs) to enter and infect cells. Because the team is working at biosafety level 2 (BSL-2), the VLPs being studied contain two proteins (glycoprotein and a matrix protein) that enable the virus to enter cells, but these VLPs lack the genes that make the intact virus so deadly. “While others are using low-throughput screening, we optimized the assay into an HTS format,” said lead author and NCATS researcher Wei Zheng, Ph.D. “Developing a new drug can take 10 to 12 years, but our approach — rapidly testing all currently approved drugs for anti-Ebola activity — offers a faster route to potential discovery of Ebola treatments.” Drawing from the NCATS Pharmaceutical Collection, a library of 2,816 approved and investigational medicines, the research team identified 53 drugs with Ebola VLP entry-blocking activity. The team identified several distinct classes of compounds, including those previously found to be microtubule inhibitors, estrogen receptor modulators, antihistamines, antipsychotics, ion channel/pump antagonists, antibiotics and anticancer drugs. Although further testing must occur before any of these drugs could be used to treat Ebola, the findings provide a jump-start to the development of such treatments. The research team has already shared its screening results, both positive and negative, with networks for Ebola drug development within NCATS; the National Institute of Allergy and Infectious Diseases, which also is part of the NIH; and the Bill & Melinda Gates Foundation. The results also will be freely available to the public through the National Library of Medicine’s PubChem database. Next steps will require a BSL-4 laboratory, where researchers could continue further evaluation of the drugs’ activities using intact virus infection assays and animal model studies. “NCATS is all about getting more treatments to more patients more quickly, and this is never more urgent than in a case of a public health emergency like Ebola,” said Christopher P. Austin, M.D., NCATS director. “This remarkable team of scientists combined NCATS’ expertise in drug screening and development with Mount Sinai’s expertise in Ebola virology to rapidly identify candidate treatments for Ebola infection.” Posted December 2014 | ||||||||
| 606 | BrIDGs Operational Model | BrIDGs staff collaborate with researchers in need of preclinical therapeutics development expertise and resources to advance candidate therapeutics into clinical trials. Researchers with sufficient preliminary data can leverage BrIDGs capabilities to execute a preclinical product development plan. In general, available expertise and contract resources include synthesis, formulation, pharmacokinetic and toxicology services. Collaborators may take advantage of these resources to obtain data and clinical-grade material for use in Investigational New Drug applications to a regulatory authority such as the Food and Drug Administration. Pre-existing intellectual property (IP) rights are retained by the owner. This allows BrIDGs to operate as a non-dilutive investment in exciting preclinical therapeutics development projects and to maximize the competitiveness of therapeutic agents for further private-sector funding. Organizations eligible to collaborate with BrIDGs include academic and nonprofit institutions, small businesses eligible for the Small Business Innovation Research program, and NIH intramural laboratories. To request a collaboration, interested parties must submit a formal proposal. These proposals are accepted on a rolling basis for the development of therapeutic agents for any disease or disorder. Studies may be proposed for a variety of therapeutic types, such as small molecules, peptides, oligonucleotides, gene vectors, recombinant proteins and monoclonal antibodies. |
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