| ID | Title | Body | Facebook Description | Facebook image | Facebook Title | Facebook Video | Twitter Description | Twitter Image | Twitter Title | Meta tags |
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| 10636 | Closing the Protein Knowledge Gap to Identify New Treatments | Each of the 20,000 genes that make up the human genome carries a set of instructions that a cell can use to make a protein. These proteins play many critical roles in human health and disease: They can transmit signals between organs, transport other molecules throughout the body and protect cells from an invading virus. But as many as 3,000 genes are considered part of the “druggable genome,” a set of genes encoding proteins that scientists already can or predict they can modify by using experimental compounds.As part of the NIH Common Fund’s Illuminating the Druggable Genome (IDG) program, a team of NCATS and other scientists recently discovered that about one in every three proteins is poorly understood. To speed this research along, NCATS scientists developed Pharos, an online portal that provides access to the protein information collected by IDG investigators. This resource is designed to help address the lack of preliminary data available for understudied proteins, in turn helping scientists further their research to close the protein knowledge gap. Read more in Nature Reviews Drug Discovery.“Our results are a starting point for future research to gain a better understanding of these understudied proteins, which can lead to new or improved treatment approaches,” said study co-author Tudor Oprea, M.D., Ph.D., of the University of New Mexico.Posted April 2018 | Investigators from IDG program recently discovered that about one in every three proteins is poorly understood, limiting research opportunities. | /sites/default/files/idg-pharos_1260x630.jpg | Closing the Protein Knowledge Gap to Identify New Treatments | Investigators from IDG program recently discovered that about one in every three proteins is poorly understood, limiting research opportunities. | /sites/default/files/idg-pharos_1260x630.jpg | Closing the Protein Knowledge Gap to Identify New Treatments | ||
| 10588 | Partner with New Therapeutic Uses | NCATS is seeking pharmaceutical company partners for its Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) program. Participating companies provide access to and information about assets that funded academic researchers test for new therapeutic uses. Supported projects have generated new knowledge and methods that improve health through smarter science. The program’s template agreements shorten the time needed to form new public-private partnerships between academic medical centers and pharmaceutical partners. Interested companies should contact NewTherapeuticUses@mail.nih.gov to discuss becoming a New Therapeutic Uses partner for the next funding opportunity. Partner Expectations NCATS coordinates funding opportunity announcements to seek promising candidates for repurposing ideas from the academic community. For these announcements, participating companies establish a template agreement and provide non-confidential information about available assets for which applicants can propose new therapeutic uses. NCATS conducts NIH peer review of all applications and supports Phase I (if needed) and/or Phase II clinical trials for meritorious projects. If a pharmaceutical partner’s assets are selected for a funded project, the company uses the template agreement to establish a collaboration with the academic investigator and provides the drug or biologic and placebo. The company also provides documentation that enables funded investigators to file or cross-reference an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA). Partner Requirements Requirements for pharmaceutical partner participation and asset selection criteria include the following: Number of Assets New pharmaceutical company partners should aim to contribute three assets to participate in a funding opportunity announcement. Asset Characteristics Mechanism of action is known. Pharmacokinetics are suitable for the mechanism to be explored in a new indication. Phase I clinical trial has been completed, and safety profile is understood. Assets currently in clinical development can be included. New molecular entities and biologics are accepted. Major Responsibilities Provide asset information to be posted on the NCATS website. View examples. Provide clinical supply for Phase I and Phase II clinical studies (drug or biologic and placebo). Provide regulatory documents (i.e., cross-reference letter or study reports) to enable a funded investigator to file an IND application in time to meet project timeline and milestones. Use template agreements that are negotiated with NCATS. View samples. Agree not to remove assets 90 days before a pre-application receipt date for a funding opportunity, unless something unanticipated (e.g., new safety information from FDA) becomes available. Become a Partner Contact NewTherapeuticUses@mail.nih.gov to discuss partnering with NCATS through the New Therapeutic Uses program. Asset lists are refreshed twice each year. | Partner with New Therapeutic Uses | Partner with New Therapeutic Uses | ||||||
| 10585 | NCATS Funds New Drug Repurposing Projects, Seeks Additional Industry Partners | Through its Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) program, NCATS recently awarded funding for three new projects to repurpose compounds that have already undergone significant research and development by industry, including testing in humans. The grantees will study graft-versus-host disease, a major problem for people who have had a bone marrow transplant; idiopathic pulmonary fibrosis, a chronic and ultimately fatal disease in which scar tissue clogs the lungs; and chronic obstructive pulmonary disease.NCATS is seeking additional industry partners to participate in future New Therapeutic Uses funding opportunities. Through the program, NCATS facilitates the establishment of efficient drug development partnerships between pharmaceutical companies and academic medical centers using template legal agreements, which accelerate the process to as few as four months, compared with the more typical nine months to a year or more. Interested companies can review participation criteria and contact NewTherapeuticUses@mail.nih.gov for more information.Posted April 2018 | NCATS is seeking additional industry partners to participate in future New Therapeutic Uses funding opportunities. | /sites/default/files/ntu-awards_1260x630.jpg | NCATS Funds New Drug Repurposing Projects, Seeks Additional Industry | NCATS is seeking additional industry partners to participate in future New Therapeutic Uses funding opportunities. | /sites/default/files/ntu-awards_1260x630.jpg | NCATS Funds New Drug Repurposing Projects, Seeks Additional Industry | ||
| 10375 | High-Throughput Combinatorial Screening Identifies Drugs that Cooperate with Ibrutinib to Kill Activated B-Cell-Like Diffuse Large B-Cell Lymphoma Cells | The clinical development of drug combinations is typically achieved through trial and error or via insight gained through a detailed molecular understanding of dysregulated signaling pathways in a specific cancer type. Unbiased small-molecule combination (matrix) screening represents a high-throughput way to explore hundreds or even thousands of drug-drug pairs for potential investigation and translation. Here we describe a high-throughput screening platform capable of testing compounds in pairwise matrix blocks for the rapid and systematic identification of synergistic, additive and antagonistic drug combinations. We use this platform to define potential therapeutic combinations for the activated B-cell-like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL). We identify drugs with synergy, additivity and antagonism with the Bruton’s tyrosine kinase inhibitor ibrutinib, which targets the chronic active B-cell receptor signaling that characterizes ABC DLBCL. Ibrutinib interacted favorably with a wide range of compounds, including inhibitors of the PI3K/AKT/mammalian target of rapamycin signaling cascade, other B-cell receptor pathway inhibitors, Bcl-2 family inhibitors and several components of the chemotherapy that is the standard of care for DLBCL. Viability of lymphoma cells treated with ibrutinib plus Bcl-2 family inhibitors. The combination responses for ibrutinib and navitoclax as judged by (A) 6×6 matrix block evaluation of ibrutinib plus navitoclax in TMD8 cells, (B) MTS assay in 96-well plates of ibrutinib plus navitoclax in the indicated lines and (C) MTS assay in 96-well plates of ibrutinib plus ABT-199 in the indicated lines. (Reprinted with permission Mathews Griner LA, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci USA. 2014;111(6): 2349-54. Copyright Proc Natl Acad Sci U S A. 2014.) Publications Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM, Liu D, Goldlust IS, Yasgar A, McKnight C, Boxer MB, Duveau DY, Jiang JK, Michael S, Mierzwa T, Huang W, Walsh MJ, Mott BT, Patel P, Leister W, Maloney DJ, Leclair CA, Rai G, Jadhav A, Peyser BD, Austin CP, Martin SE, Simeonov A, Ferrer M, Staudt LM, Thomas CJ. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci USA. 2014;111(6): 2349-54. Public Health Impact A common strategy for killing cancer cells is to target a protein that is critical for their survival and growth. Often, targeting one protein is not effective at killing cancer cells, as they can find alternative methods to survive. This study found that using ibrutinib in combination with many other cancer drugs works better to kill cancer cells than each tested drug by itself. This knowledge can be used to set up studies to test treating cancer patients with a combination of ibrutinib and other drugs. | /sites/default/files/Ibrutinib_jpeg.jpg | High-Throughput Combinatorial Screening Identifies | /sites/default/files/Ibrutinib_jpeg.jpg | High-Throughput Combinatorial Screening Identifies | ||||
| 10372 | PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability | Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1 (P3F). The mechanisms by which P3F dysregulates chromatin are unknown. This study found that P3F reprograms the cis-regulatory landscape by inducing (de novo) super enhancers (SEs). P3F uses SEs to set up autoregulatory loops in collaboration with master transcription factors MYOG, MYOD and MYCN. This myogenic SE circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small molecule inhibition of protein targets induced by or bound to PAX3-FOXO1-occupied SEs. Furthermore, P3F recruits and requires BET bromodomain protein BRD4 to function at SEs, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield novel insights into the epigenetic functions of P3F and reveal a specific vulnerability that can be exploited for precision therapy. Molecular Sensitivity Landscape of Fusion-Positive Rhabodomyosarcoma (FP-RMS) Is Enriched in SE-Associated Targets, Including BRD4 (A) Potency in PAX3-FOXO1 rhabdomyosarcoma cell lines versus toxicity in normal cell lines, measured by dose response and summarized across 240 mechanistically distinct subcategories. The percent area under the dose response curve (%AUC) was averaged for all compounds within a target subcategory. The number of compounds in each category is indicated by the size of the bubble, and the difference in %AUC (normal −RMS) is indicated by color scale. (B) Differential sensitivities against molecules targeting proteins associated with SEs, compared with non-SE targets and SE signal transduction. The size of the bubble indicates the number of molecules against each target. (Reprinted with permission from Gryder BE, et al. PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov. 2017;7(8):884-99. Copyright Cancer Discov 2017.) Publications Gryder BE, Yohe ME, Chou HC, Zhang X, Marques J, Wachtel M, Schaefer B, Sen N, Song Y, Gualtieri A, Pomella S, Rota R, Cleveland A, Wen X, Sindiri S, Wei JS, Barr FG, Das S, Andresson T, Guha R, Lal-Nag M, Ferrer M, Shern JF, Zhao K, Thomas CJ, Khan J. PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov. 2017;7(8):884-99. Public Health Impact Cancer growth is driven by various genetic mutations that cause fast growth and evasion of cell death. This study found that rhabdomyosarcoma cells have a specific mutation that alters the gene expression within the cells and makes these cancer cells sensitive to certain drugs. This knowledge can be used to do more testing of these specific drugs in patients with rhabdomyosarcoma. | /sites/default/files/Rhabo_jpeg.jpg | PAX3-FOXO1 Establishes Myogenic Super Enhancers | /sites/default/files/Rhabo_jpeg.jpg | PAX3-FOXO1 Establishes Myogenic Super Enhancers | ||||
| 10346 | Active Chemistry Technology Projects | The discovery of mechanistically defined bioactive small molecules continues at a breakneck pace. Whether they are approved drugs or preclinical probe compounds, understanding how different biological systems respond to these tools is a critical step in broadening our basic understanding of systems biology and the translational potential of mechanistic perturbation. Our team utilizes a variety of chemistry technologies to develop new, mechanistically defined small molecule tools. We also survey the scientific literature to find and collect new and exciting small molecules to populate our chemogenomics screening libraries. Our primary library is called the Mechanistic Interrogation PlatE (or MIPE). We are currently on the sixth generation of this library which is used in a myriad of phenotypic screening studies across NCATS teams. For key target classes (like kinase inhibitors), we also conduct profiling efforts to gauge selectivity and the possibility for off-target positioning into new indications or as the starting point for new polypharmacology-informed optimization efforts. Highlights from our small molecule discovery work include the first reported small molecule activators of the M2 isoform of pyruvate kinase and a recently disclosed dual FLT3/IRAK1/4 inhibitor. While we don’t set out to discover new drugs, several agents discovered in our lab have moved into human clinical evaluations, including Zalunfiban and 2R,6R-hydroxynorketamine.Discovery of Small Molecule PKM2 ActivatorsPyruvate kinase catalyzes the transformation of phosphoenolpyruvate and ADP to pyruvate and ATP and is the penultimate step in the glycolytic process. The M2 isoform is catalytically inactive and rate limiting. Certain cells, including most cancer cells, choose to express this isoform to support the metabolic program of rapidly proliferating cells. Collaborating with the Cantley and Vander Heiden labs, our team discovered and optimized the first small molecule activators of PKM2. These agents helped confirm the role of PKM2 in cancer cell metabolism and expanded our understanding of the role of this enzyme in several other phenotypes, including inflammation (Anastasiou, et al. Science 2011, 334, 1278-1283 and Palsson-McDermott, Cell Metabolism, 2015, 21, 65-80). | Active Chemistry Technology Projects | Active Chemistry Technology Projects | ||||||
| 10343 | Completed Chemistry Technology Projects | Click on the links below to view completed Chemistry Technology projects: A BODIPY Conjugate of the BCR-ABL Kinase Inhibitor Nilotinib A Role for RDEA-119 Within the Treatment of Marfan Syndrome A Role for Tofacitinib Within the Treatment of Adult T Cell Leukemia and HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis BMS-509744 as Chemical Probe for Studying the Role of Inducible T Cell Kinase in HIV Replication Incorporating Stable Glycosides into Novel Small Molecule Scaffolds Inhibitors of NAD-Dependent 15-Hydroxyprostaglandin Dehydrogenase for the Study of Prostaglandin's Role in Inflammation Small Molecule Combinations for Basic and Translational Studies | Completed Chemistry Technology Projects | Completed Chemistry Technology Projects | ||||||
| 10262 | CTSA Program Support Enables Innovative Study of Brain Function | Fiza Singh, M.D., who received funding from the University of California, San Diego, Altman Clinical and Translational Research Institute. To create memories, the brain must be able to activate nerve cells called neurons and make them “fire” in sync. Brain waves are created by this repetitive activity, and they come in different frequencies. Gamma waves are the highest (fastest) frequency, and researchers believe these waves are connected to cognitive functions like memory. When gamma waves are out of sync, problems with memory also occur. But whether altered gamma waves actually cause faulty memory remains unclear. To further investigate this potential link, Fiza Singh, M.D., received grant support from the University of California, San Diego, Altman Clinical and Translational Research Institute, an NIH NCATS Clinical and Translational Science Awards (CTSA) Program hub. Singh set out to determine whether people with schizophrenia, who have both altered gamma waves as well as memory problems, can “correct” their gamma waves, which could potentially help them improve their memory. To test her theory, Singh created a visual display on a computer monitor of an individual’s gamma waves in the form of an airplane. Disorderly brain waves made the plane fly erratically, and the person attempted to “make” the plane fly smoothly just by thinking about it. And it worked! The results of Singh’s pilot study were so promising that NIH’s National Institute of Mental Health (NIMH) has awarded her a five-year exploratory research project grant to assess whether “training” people with schizophrenia to influence their own gamma waves will improve their memory. The potential applications of this research extend beyond schizophrenia to many other forms of mental illness, which could one day be addressed using a headset connected to a smartphone. This approach could enable individuals to “see” their brain being depressed or anxious and exert some control in moving toward a healthier state of mind. Read more about this research. Posted April 2018 | A CTSA Program-funded researcher tests innovative training to help people with schizophrenia “correct” disordered brain waves. Results suggest the training could potentially help improve memory. | /sites/default/files/singh_1260x630.jpg | CTSA Program Support Enables Innovative Study of Brain Function | A CTSA Program-funded researcher tests innovative training to help people with schizophrenia “correct” disordered brain waves. Results suggest the training could potentially help improve memory. | /sites/default/files/singh_1260x630.jpg | CTSA Program Support Enables Innovative Study of Brain Function | ||
| 10135 | Patient Perspectives and Hope of Research Defined Annual Rare Disease Day at NIH | Translational Science Highlight Involving patients and their perspectives at every stage of the translational science process helps ensure research outcomes will be most relevant and more readily adopted. About 7,000 rare diseases affect roughly one in 10 people in the U.S. Less than 5 percent of these conditions have a treatment approved by the Food and Drug Administration (FDA). On March 1, 2018, more than 700 patients, scientists, policymakers and others participated in the annual Rare Disease Day at NIH to learn more about these disorders and the research that is providing hope. Rare Disease Day at NIH is co-hosted by NCATS and the Clinical Center. Christopher P. Austin, M.D., NCATS director, provided opening remarks, noting that patients’ voices were the most crucial factor in the day’s upcoming agenda. The 2018 event was organized around four panel discussions, each of which included a rare disease patient or family member. Participants learned about translating the technique of gene editing into new treatments, how patient groups can help advance research progress, some of the challenges presented by gene therapy, and the experiences of young adults living with a rare disease. NCATS Director Christopher P. Austin, M.D., welcomed attendees to the annual Rare Disease Day at NIH. Daniel Soñé Photography. Advances in Gene Editing The first panel discussion focused on a case study of gene editing, which is a new approach for treating rare diseases, since many of these conditions are caused by a problem with a particular gene. Gene editing, also known as genome editing, aims to change the DNA sequence so that genes may be able to work better and tell the body to make proteins that are more functional. Although she’d been sick since childhood, Erica Thiel wasn’t diagnosed with the rare disease mucopolysaccharidosis (MPS) until the age of 21. Since then, she has received a weekly six-hour treatment to replace a protein that her body doesn’t make correctly. This therapy costs $24,000 a week. “Better treatments are needed,” Thiel told the audience. “I hope that these advances and the promise of gene editing can save other families from the many challenges that I have faced.” Erica Thiel was diagnosed with a rare disease at age 21. Daniel Soñé Photography. In disorders like MPS, cells cannot effectively get rid of “waste” (caused by normal cell turnover). Sangamo Therapeutics recently began the first clinical trials in humans of a gene editing product intended to correct this problem in one form of MPS. As of March 1, only two people had received the product. Sandy Macrae, Ph.D., M.B., Ch.B., president and chief executive officer of Sangamo, said the company will soon begin testing a similar method for treating another form of MPS and a type of hemophilia, a blood-clotting disorder. “If this works, it could become a platform where you can drop in other genes,” he said. NIH is working to advance the science of gene editing through the Somatic Cell Genome Editing program, a new NIH Common Fund effort led by NCATS. Goals include expanding the number of gene editing tools available to researchers. It is hoped that advances in technologies like the one Sangamo is testing could make it possible to someday use gene editing to treat thousands of genetic diseases. Getting Involved in Research A common theme throughout the day was how patients and their caregivers can be involved in research. “Patients are the best source of information on rare diseases,” said Marshall Summar, M.D., chair of the board of directors for the National Organization for Rare Disorders and director of the Rare Disease Institute at Children’s National Health System, where he is also chief of the Division of Genetics and Metabolism. “Given the genetic variation even within a single disease, each family becomes the world expert on their own version of that disease.” Summar specializes in a group of rare diseases known as urea cycle disorders. In the 1980s, a child born with a urea cycle disorder had a less than 5 percent chance of surviving to age 5. Now the same child’s chance would be more than 95 percent. This advance came about because patients, caregivers and researchers collaborated to take what they already knew and share it so that everyone could follow the same best practices. “The take-home message is not that it’s nice to collaborate,” Summar said. “It’s key to the survival of patients.” Providing information to the patient community about research opportunities is one of the most important roles a patient organization can play. Theresa Strong, Ph.D., co-founded an organization focused on the rare disease Prader-Willi syndrome. Daniel Soñé Photography. “We can educate our patients about clinical trials, so when the trials come along, they will be ready,” said Theresa Strong, Ph.D., co-founder and director of research programs for the Foundation for Prader-Willi Research. “We also can assist pharmaceutical companies and regulatory agencies in understanding the needs of the patient community.” For patients and caregivers who are wondering how to get started, NCATS offers resources such as the Toolkit for Patient-Focused Therapy Development. The toolkit is a collection of resources that can help organizations advance research on rare and common diseases, including information on topics ranging from how to start a nonprofit to how to participate in meetings with the FDA. Challenges of Gene Therapy For the third panel discussion, participants focused on some of the challenges of treatments that involve fixing or supplying corrected versions of genes. “For about two decades, people have thought we were on the cusp of gene therapy,” said Peter Marks, M.D., Ph.D., director of the FDA Center for Biologics Evaluation and Research. “I think we are looking, in the next 5 to 10 years, for this to take off in an exponential manner.” This treatment approach is now a reality; the FDA approved the first gene therapy for an inherited disorder—a rare eye disease—in December 2017. One of the challenges for developing gene therapies is choosing the right component to measure in clinical trials. “It’s important to show the person’s cells are making a protein they weren’t making before, but that isn’t the only thing that matters,” Marks said. “The FDA ultimately needs to know whether a treatment is having an effect on how the patient feels, functions or survives.” This focus on results that are meaningful to patients rings true to Maria Kefalas, Ph.D., co-founder of the Calliope Joy Foundation. She has helped children enroll in clinical trials for a gene therapy for the rare disease metachromatic leukodystrophy. She cautioned that the current experimental treatment, which is quite promising for some patients who are now walking and talking when they wouldn’t normally be able to do so, is not a cure and that it does not work for all. “It’s been very difficult to talk to families about what can happen, because we have these incredible success stories, and then we have kids for whom the treatment isn’t nearly as effective,” she said. Maria Kefalas, Ph.D. (right), co-founder of the Calliope Joy Foundation, spoke to attendees about helping children access clinical trials. Pictured on the left is Kristin Smedley, president of the Curing Retinal Blindness Foundation. Daniel Soñé Photography. These challenges are top of mind for NCATS scientists who have supported gene therapy projects for rare diseases, including one for Pompe disease, a muscle disorder, and another for aromatic L-amino acid decarboxylase (AADC) deficiency, a pediatric condition that causes developmental delays. While these scientific advances offer hope for new treatments, more work lies ahead to meet the needs of all rare disease patients who could benefit from gene therapy. Living with Rare Diseases The final panel of the day featured young adults sharing their experiences about living with a rare disease or the risk of developing one. For example, it can be frustrating to not be taken seriously by clinicians. Taj Neaz Powell has often found himself in the emergency room in acute pain as a complication of sickle cell disease. His arms are scarred from the many blood transfusions and intravenous medications required to treat the disease. Taj Neaz Powell (right), a patient at The Children’s Inn at NIH, talked about the challenges of living with sickle cell anemia. Pictured on the left is Eric Sid, M.D., M.H.A., of NCATS’ Office of Rare Diseases Research. Daniel Soñé Photography. “The doctors would take one look at my arms and say, ‘Oh, he’s a drug addict,’” Powell said. “Unless my doctor called or my parents would come in, sometimes they wouldn’t give me the benefit of the doubt.” Maddie Shaw, founder of Maddie’s Herd, reported similar experiences while trying to get a diagnosis. “I was told multiple times that I was being overdramatic or sensationalizing things as a tween girl looking for some excitement in her life,” she said. Shira Strongin, founder of Sick Chicks, is still undiagnosed and often finds it frustrating that clinicians address her mother instead of her. “Our voices are valid and should be listened to as experts in our own body and for our own health,” she said. “Be your own expert, your own best advocate.” Taylor Kane, founder of Young ALD (Adrenoleukodystrophy) Carriers as well as Remember the Girls, carries the gene that caused her father’s fatal illness and is likely to eventually develop symptoms herself. She emphasized that there is power in working with other people living with rare diseases, underscoring the overall purpose of Rare Disease Day: “Rare is rare, but rare is powerful when we come together.” Strength in Numbers Austin underscored the message of “power in numbers” in his closing remarks, emphasizing the hope and scientific advancements that come from sharing resources and data from different diseases to create more knowledge and connections. “Consortia in the Rare Diseases Clinical Research Network work together to understand and treat related diseases,” he said, adding that NCATS and its NIH partners are completely committed to doing whatever is possible to speed up progress. “If we stick together as a community, as is happening now, the future is very bright indeed.” Posted April 2018 | On March 1, 2018, patients, scientists, policymakers and others participated in the annual Rare Disease Day at NIH. | /sites/default/files/rdd-2018_1260x630.jpg | Patient Perspectives and Hope of Research Defined Annual RDD | On March 1, 2018, patients, scientists, policymakers and others participated in the annual Rare Disease Day at NIH. | /sites/default/files/rdd-2018_1260x630.jpg | Patient Perspectives and Hope of Research Defined Annual Rare RDD | ||
| 10005 | NCATS Supports Award-Winning Technology for Drug Development | Translational Science Highlight NCATS supported an innovative platform technology to precisely deliver nutrients and hormones to cells for a preclinical therapeutics testing program. The adaptability of the technology to other translational science applications led to additional funding for its commercialization and supports NCATS’ goal of making drug development more efficient. Most potential drugs fail in clinical trials despite showing promising results in preclinical studies. Thirty percent of these drugs fail because they prove to be too toxic. Not only do these failures delay getting new treatments to patients, they also put patients at risk. To address this challenge in drug development, NCATS supported research on a device designed to make the preclinical drug testing process more efficient and reliable. Essentially a series of pumps and valves controlled by a computer, the MultiWell MicroFormulator enables researchers to mix and deliver very small amounts of drugs or other solutions to laboratory cell models quickly and automatically. The 96-well plate is a standard tool for screening drugs for their effects on cells, with each well serving as a tiny test tube. With the MultiWell MicroFormulator, researchers can independently control the addition and removal of solution for each well, allowing them to run 96 different experiments simultaneously in one plate. The transformative potential of the new device was acknowledged with an R&D 100 Award from R&D Magazine in late 2017. Commonly referred to as the “Oscars of Innovation,” the R&D Awards recognize the most pioneering technologies of the year. John P. Wikswo, Ph.D., professor at Vanderbilt University and director of the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE), developed the MultiWell MicroFormulator with NCATS’ support through its Tissue Chip for Drug Screening (Tissue Chip) and Small Business Innovation Research (SBIR) programs. “The MultiWell MicroFormulator provides researchers a level of control over cell studies not previously possible,” Wikswo said. “It’s a revolutionary concept.” Better Models for Predicting Drug Response John Wikswo, Ph.D. (right), director of Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE), and Ronald Reiserer (left), laboratory manager of VIIBRE, receiving an R&D 100 Award from R&D Magazine for the MultiWell MicroFormulator. One reason translating preclinical knowledge about a potential drug to the clinic can be difficult is that cell and animal models have inherent limitations. Human cell cultures, grown in the laboratory in a plate or dish, are more simplistic than the multiple cell types and 3-D structure that make up organs and tissues in the body. Animal models have biological differences from humans that can affect how a drug is metabolized and how well it works. And some diseases cannot be modeled in laboratory animals at all. Through the development of tissue chips or “organs-on-chips,” which consist of live human tissues on a small chip, NCATS seeks to reproduce the biology and physiology of organs and tissues and model diseases in unprecedented ways. NCATS — in collaboration with nine other NIH Institutes and Centers and the U.S. Food and Drug Administration — leads the Tissue Chip program, which is designed to improve the translational science process for predicting whether drugs will be safe and effective in humans. Wikswo’s team at Vanderbilt was among 12 grantees funded in 2012 to develop tissue chips that modeled a specific organ or tissue. Using supplemental funding to model additional organs, Wikswo realized that he could engineer pumps and valves to deliver hormones or nutrients to a tissue chip system that would essentially stand in for a missing organ. This sparked the idea for the MicroFormulator, a simplified version of the award-winning device. An early version of the MultiWell MicroFormulator delivered to AstraZeneca. (Vanderbilt University) After seeing Wikswo present on the MicroFormulator, the pharmaceutical company AstraZeneca approached him about adapting the device to address another challenge in drug development. When a person takes a drug, the concentration of the drug rises in the blood, reaches a maximum level, and then gradually tapers off. This process, known as a pharmacokinetic profile, is very different from adding a drug to cells in a dish or plate all at once. The company realized the device could both add a drug to and remove it from cells in a timed fashion, mimicking a real-world pharmacokinetic profile. But they wanted the device adapted to the standard 96-well plate so that it could quickly test different pharmacokinetic profiles for a given drug to identify which profile led to the best effect in cells. With that knowledge in hand, the research team could go back and modify the drug to achieve that profile. In 2016, NCATS awarded SBIR funding for the project through CFD Research Corporation in Huntsville, Alabama, which was working with Wikswo on similar devices. The award supported hardware development as well as a computer programmer who created the software to control the pumps and valves. The MultiWell MicroFormulator project soon achieved the ultimate goal for SBIR awards: commercialization. The U.K. biotechnology company CN Bio Innovations licensed the device in 2017. “The software development was absolutely critical to the survival of the project,” Wikswo said. “There was marvelous confluence between the NCATS SBIR program, the needs of AstraZeneca, and the work we were doing on pumps and valves with Tissue Chip program support.” Improving Drug Screening with 3-D Printed Tissues NCATS also saw another potential application for the technology: to adapt it for use in 3-D bioprinted tissues. The NCATS bioprinting team creates human tissue from cells, printing them on standard cell plates to use for drug screening in place of traditional cell culture, which is just a single layer of cells. Growing tissues in plates rather than on chips has challenges. Tissue thickness requires laboratory staff to repeatedly change the culture solutions to supply the tissue with fresh nutrients and remove waste. The process is time-consuming, and removing the cells from the incubator exposes the tissues to stressful changes in temperature. In between solution changes, the tissues sit in their own waste, which does not happen in the body. All of these stresses affect how well the cells mature into a native-like tissue. Early version of the SmartLid, which will be delivered to the NCATS 3-D Bioprinting Laboratory later in 2018. (Vanderbilt University) With additional NCATS SBIR support awarded in 2017, Wikswo and his partners at CFD Research Corporation are now close to completing work on a first version of a device called a “SmartLid.” The SmartLid will change the culture media automatically and continuously while the tissue plates remain in the incubator, which keeps the tissues at their preferred temperature and oxygen level. The idea is to help tissues mature more efficiently and successfully, leading to an increase in reproducible research. “Having a standardized and scalable process for maintaining tissues and monitoring their maturation will be a major advance in the field,” said Marc Ferrer, Ph.D., 3-D bioprinting team lead in the NCATS Division of Preclinical Innovation. Wikswo noted the importance of having support at different stages of the technology development process, from inception to getting the MultiWell MicroFormulator across the finish line to commercialization. “There are many challenges in the tissue field,” said Lucie Low, Ph.D., program manager for the Tissue Chip program at NCATS. “This is a nice example of how, working collaboratively with academia and industry, we can spur progress in the field to ultimately deliver more treatments to patients more quickly.” Posted March 2018 | To address challenges in drug development, NCATS supported research on a device designed to make the preclinical drug testing process more efficient and reliable. | /sites/default/files/vanderbilt-rw_1260x630.jpg | NCATS Supports Award-Winning Technology for Drug Development | To address challenges in drug development, NCATS supported research on a device designed to make the preclinical drug testing process more efficient and reliable. | /sites/default/files/vanderbilt-rw_1260x630.jpg | NCATS Supports Award-Winning Technology for Drug Development |
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