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| 9093 | NIH Collaboration Leverages CTSA Program for Research Mentoring | Bo Yu, D.D.S., Ph.D., received a CTSA Program Mentored Career Development Award to develop and test a treatment for periodontitis. The experience is helping him learn the science of translation — moving from basic research toward clinical applications. NIH’s National Institute of Dental and Craniofacial Research (NIDCR) is collaborating with NCATS through the Clinical and Translational Science Awards (CTSA) Program to provide translational research training opportunities to oral, dental and craniofacial scientists early in their careers. Through supplemental funding to the program’s Mentored Career Development Awards, NIDCR is supporting career development of five investigators conducting research in oral, dental and craniofacial disease and prevention. This pilot effort was initiated in response to a 2014 Physician-Scientist Workforce Working Group Report (PDF - 6.2MB) to the Advisory Committee to the NIH Director that highlighted the need for greater representation of dentist-scientists in the physician-scientist workforce. The report also recommended that NIH Institutes and Centers leverage the CTSA Program hubs for training and career development of early-career physician-scientists. “The CTSA Program hubs offer unique resources and expertise in translational research and team science,” said Lynn Mertens King, Ph.D., chief of NIDCR’s Research Training and Career Development Branch. “NIDCR’s supplements afford the oral, dental and craniofacial research community additional opportunities to participate in mentored clinical research career development and will help these scientists transition to an independent career.” Through their participation in the program, scholars have more time set aside for research, mentoring from diverse investigators, and opportunities to hone grant-writing and other skills needed for a successful research career. The five scholars and CTSA Program hubs are: Ejvis Lamani, D.M.D., Ph.D., at the University of Alabama at Birmingham Center for Clinical and Translational Science Annie Chou, D.D.S., Ph.D., at the University of California, San Francisco (UCSF) Clinical & Translational Science Institute David Reed, Ph.D., at the University of Illinois at Chicago Center for Clinical and Translational Science Bo Yu, D.D.S., Ph.D., at the University of California, Los Angeles (UCLA) Clinical and Translational Science Institute Jin Xiao, D.D.S., Ph.D., at the University of Rochester Clinical & Translational Science Institute Their projects represent the broad spectrum of NIDCR-supported research, from studying the oral yeast and bacteria of infants to identify risk factors for severe early-childhood caries to evaluating treatment strategies for people with Sjögren’s syndrome, an autoimmune condition that affects oral health. “Receiving this award has been an eye-opening experience,” said Yu, an assistant professor at the UCLA School of Dentistry. “My mentoring team has rich experience in basic science, public health, and bioengineering and provides the perspective I was not able to get from the dental school alone.” The NIH collaboration expands the reach of translational science training conducted at the participating CTSA Program hubs. NCATS and NIDCR also hope the impact of the pilot will extend far beyond the individual scholars to other investigators in the schools of dentistry. This has certainly been the case at UCLA, according to Yu: “My involvement in the CTSA Program has led to a strong encouragement for a team science approach in the dental school and to forming more collaborations throughout the campus.” Posted February 2018 | NCATS’ CTSA Program and NIDCR collaborate to provide oral, dental and craniofacial scientists with translational research training opportunities early in their careers. | /sites/default/files/nidcr_900x600.jpg | NIH Collaboration Leverages CTSA Program for Research Mentoring | NCATS’ CTSA Program and NIDCR collaborate to provide oral, dental and craniofacial scientists with translational research training opportunities early in their careers. | /sites/default/files/nidcr_900x600.jpg | NIH Collaboration Leverages CTSA Program for Research Mentoring | ||
| 8937 | NCATS-Led Team Finds Potential Strategy to Fight Huntington’s Disease | January 11, 2018A team of NIH scientists and collaborators has uncovered a new potential strategy against Huntington’s disease, an inherited, fatal neurodegenerative disorder that has no cure. In a study published recently by eLife, researchers at NIH’s National Center for Advancing Translational Sciences (NCATS), the University of Michigan and Baylor College of Medicine demonstrated that blocking the activity of an enzyme called PIP4Kγ reduced the effects of the disease in both cell and animal models. The findings indicate that inhibiting the enzyme triggers a normal-cell-“recycling” system that helps lessen the buildup of malformed, toxic proteins in brain cells that is associated with neurological problems.In Huntington’s disease, a single faulty gene causes a progressive breakdown of nerve cells in the brain and severe physical and neurological damage leading to death. Early symptoms of Huntington’s disease, such as uncontrolled movements or difficulty focusing, typically begin in a person’s 30s or 40s; over time, people with the disorder lose the ability to move, speak and think. About 30,000 people in the U.S. have the disease.In a cell model of Huntington’s disease, the compound NCT-504 lowers the amount of toxic protein in the cell by inhibiting the enzyme PIP4Kγ. Here, the panels show cells before (top) and after treatment (bottom) with NCT-504. The right column indicates the abundance of the toxic protein. The cells after treatment with NCT-504 show a significant decrease in toxic protein accumulation.A common characteristic among many neurodegenerative disorders is a breakdown in the cell’s ability to discard its cellular waste, a process called autophagy. In autophagy, damaged proteins and worn-out cellular components are delivered to the cell’s lysosome, a compartment where these components are broken down by enzymes and recycled. Cells can use this process to clear out the accumulation of disease-causing proteins, including those found in Huntington’s disease. In Huntington’s, however, autophagy is less effective than usual, leading to a toxic buildup of cellular waste.In earlier work, co-author Juan Marugan, Ph.D., acting branch chief and group leader of the NCATS Chemical Genomics Center, and his NCATS colleagues tested thousands of compounds against the toxic Huntington’s protein in diseased cells. Scientists know that high levels of the protein in cells play a role in neurological defects in the disease. The team found that one compound, NCT-504, lowered the level of Huntington’s protein in the cells and improved the cells’ survival.Marugan and his colleagues subsequently discovered that the compound worked by blocking PIP4Kγ activity. To better understand how this related to Huntington’s disease, the NCATS group, including co-authors Marc Ferrer, Ph.D., and Noel Southall, Ph.D., collaborated with co-author Lois Weisman, Ph.D., and her research team at the University of Michigan Life Sciences Institute in Ann Arbor.The researchers knew that PIP4Kγ plays a role in cell signaling, a process by which cells send chemical messages to communicate information for biological activities. The team used NCT-504 to inhibit PIP4Kγ activity in various cells, including connective tissue cells from Huntington’s disease patients and human and mouse neurons from Huntington’s models. This inhibition of PIP4Kγ increased recycling activity and reduced the clusters of Huntington’s proteins in the cells.The researchers also wanted to see what would happen if they genetically turned off PIP4Kγ activity. Co-author Juan Botas, Ph.D., Baylor College of Medicine in Houston, and his colleagues studied two different Huntington’s models, using fruit flies. The fruit fly model has been shown to mimic many of the effects of Huntington’s disease in humans. The neurons of Huntington’s fruit fly models are littered with toxic Huntington’s proteins. Silencing PIP4Kγ activity reduced the amount of Huntington’s disease protein that accumulated in fruit fly neurons, lessening the damage to the neurons and improving the flies’ ability to move.“These results provide important insights into understanding the biology of a rare, devastating neurological disease,” said Marugan. “PIP4Kγ inhibitors could be useful for Huntington’s and other neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, which also are marked by the accumulation of toxic proteins.”Marugan and his colleagues plan to continue to evaluate molecules that are more efficient at blocking the enzyme. “We want to develop better molecules that could intervene in Huntington’s and potentially other diseases,” he said.The research was supported by NCATS through its Intramural Research Program; National Institute of Neurological Disorders and Stroke grants R01-NS064015, R01-NS099340 and R01-NS097542 National Institute on Aging grant P30-AG053760; the American Heart Association; and the University of Michigan through its Protein Folding Diseases Initiative. | A team of NCATS scientists and collaborators have uncovered a potential strategy against Huntington’s disease that may also be relevant to a range of neurodegenerative disorders. | /sites/default/files/huntington_1260x630.jpg | NCATS-Led Team Finds Potential Strategy to Fight Huntington’s Disease | A team of NCATS scientists and collaborators have uncovered a potential strategy against Huntington’s disease that may also be relevant to a range of neurodegenerative disorders. | /sites/default/files/huntington_1260x630.jpg | NCATS-Led Team Finds Potential Strategy to Fight Huntington’s Disease | ||
| 8936 | NCATS’ Preclinical Collaboration Enables Gene Therapy for Rare Muscle Disease to Advance to Clinical Trial | Translational Science Highlight NCATS scientists collaborated with NIH-funded researchers at Duke University to advance a gene therapy for a rare neuromuscular disorder toward clinical testing. The work also has implications for other diseases because it shows how gene therapy can affect the immune system. NCATS Therapeutics for Rare and Neglected Diseases (TRND) researchers and scientists at Duke University’s Clinical and Translational Science Institute (CTSI) have helped advance a gene therapy for Pompe disease into clinical testing for the first time. Patients with this rare, often deadly muscle disorder have a faulty gene that does not make enough of an enzyme, acid alpha-glucosidase (GAA), needed to break down glycogen — sugar stores — in the body. Glycogen buildup in muscle cells results in abnormal development; if left untreated, Pompe disease can lead to respiratory problems, heart failure and death. This therapy uses a modified virus to deliver a healthy gene to a patient’s liver, which then acts like a GAA factory, churning out the missing enzyme into the bloodstream and to muscle cells. “We completed experiments demonstrating the advantages of gene therapy for Pompe disease in mouse models and had convincing evidence for its use in patients,” said principal investigator Dwight Koeberl, M.D., Ph.D., a medical geneticist and professor of pediatrics at Duke University. “A collaboration with NCATS, through its TRND program, helped overcome therapy development obstacles — including manufacturing a virus supply needed to deliver the healthy gene and navigating the complex regulatory development processes — to make clinical testing possible.” This is an illustration of this gene therapy approach for Pompe disease, a deadly, inherited muscle disorder caused by a faulty gene. This image depicts a modified virus, called rAAV 8, being injected into an individual and carrying a healthy gene to the liver. Once in the liver, the gene produces a missing enzyme, called GAA, which goes to the muscles and helps them work. Based on mouse studies, the researchers also expect the gene therapy to train the body’s immune system to recognize GAA and not attack it. Koeberl and Duke University School of Medicine scientists will begin a clinical trial in fall 2018 funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, with support from NCATS, to determine the safety of the therapy in 20 Pompe disease patients. “NCATS’ collaborative preclinical research led to the demonstration of a promising gene delivery approach,” said Nora Yang, Ph.D., director of portfolio management and strategic operations in NCATS’ Division of Preclinical Innovation, where the TRND program is administered. “The rare disease focus of this project made it a natural fit with the TRND program, and it adds to NCATS’ growing experience with different gene therapy platforms.” The current standard treatment for Pompe disease is enzyme replacement therapy (ERT), in which the missing GAA enzyme is directly injected into the body. Although ERT can be effective for many patients, it is expensive, requires injection every two weeks, and may not work for all patients with Pompe disease, especially those whose immune systems recognize the injected GAA as a foreign substance and attack the enzyme. Even for those patients in whom ERT initially works, the body can develop an immune response and eventually build a resistance to the therapy. Last year, Koeberl’s team showed in animal studies that gene therapy appeared to cause the animals’ immune systems to recognize GAA so they wouldn’t attack it, making ERT more effective. ERT worked better in mice with Pompe disease even when the gene therapy doses were too low to produce enough GAA to improve muscle function. The researchers also showed that a small, single dose of gene therapy could be as effective as – or more effective than – ERT. They found that when Pompe disease mice produced high enough levels of GAA, the animals no longer needed ERT after gene therapy. “We would like to see this promising new therapy added to the ‘medicine chest’ for physicians to help treat and manage all patients with Pompe disease,” Yang said. “If the concept of using gene therapy to build immune tolerance works, there is the potential that we can apply the same principle to other diseases that involve problems with immune system intolerance for ERT to help many more patients who suffer from debilitating diseases.” The research was supported by NCATS through its TRND program, NIAMS grants R01-AR065873, U01-AR071693 and U34-AR064515, and Genethon. Through its TRND program, NCATS scientists provide preclinical expertise and resources to move a potential therapy toward an Investigational New Drug (IND) application, which is required by the Food and Drug Administration prior to clinical testing. In limited cases, NCATS also provides TRND support for proof-of-concept human clinical studies. Posted January 2018 | NCATS and Duke University scientists help advance a gene therapy for Pompe disease into clinical testing for the first time. | /sites/default/files/trnd-pompe_1260x630.jpg | NCATS Collaboration Enables Gene Therapy to Move to Clinical Trial | NCATS and Duke University scientists help advance a gene therapy for Pompe disease into clinical testing for the first time. | /sites/default/files/trnd-pompe_1260x630.jpg | NCATS Collaboration Enables Gene Therapy to Move to Clinical Trial | ||
| 8874 | Todd B. Sherer, Ph.D. (2020) | Todd B. Sherer, Ph.D., is chief executive officer of The Michael J. Fox Foundation for Parkinson’s Research. He joined the Foundation in 2004 as scientific manager, becoming vice president for research programs in 2006. Currently, he directs the Foundation’s research portfolio, identifies optimal scientific approaches and develops strategic priorities for the Foundation’s mission of improving treatments for and, ultimately, curing Parkinson’s disease. Sherer acts as the Foundation’s spokesman, presenting scientific and clinical findings to lay audiences and engaging patient groups and pharmaceutical partners. Sherer serves on the Parkinson’s Action Network Board of Directors. He received his doctorate in neuroscience from the University of Virginia in 1999 and completed his postdoctoral studies on Parkinson’s disease at Emory University. | Dr. Sherer is chief executive officer of The Michael J. Fox Foundation for Parkinson’s Research. | Todd B. Sherer, Ph.D. (2015) | Dr. Sherer is chief executive officer of The Michael J. Fox Foundation for Parkinson’s Research. | Todd B. Sherer, Ph.D. (2015) | ||||
| 8847 | Development of Dual-Acting IRAK/FLT3 Inhibitors for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) | MDS and AML are blood cell cancers with a large patient burden. Collectively, more than 30,000 new cases of MDS and AML are diagnosed in the United States each year. Patients are typically treated with chemotherapy and, in some cases, stem cell transplantation, but durable remission often remains elusive. As a result, the median survival time for MDS is only 2.5 years after diagnosis, and the 5-year survival rate for AML is only 27 percent. Improved treatments for MDS and AML are urgently needed. Scientific Synopsis The IRAK1/4 and FLT3 kinase enzymes play key roles in cell signaling pathways that drive the progression of MDS and AML. Small molecule inhibitors of FLT3 have advanced into Phase II clinical trials and have demonstrated proof-of-concept in the treatment of AML. However, these initially promising results have been tempered by the realizations that inhibition of FLT3 signaling can lead to increased compensatory signaling through the IRAK pathway and that cancerous cells can develop mutant forms of FLT3 that are not blocked by the first-generation inhibitors. Both the compensatory signaling through IRAK and the development of FLT3 mutations render single-acting FLT3 inhibitors less effective over time. The goal of this project is to develop dual-acting inhibitors of both IRAK and FLT3. Small molecule inhibitors that block signaling through both pathways and that inhibit not only the most common form of FLT3 but also its mutant forms should be more effective as long-term treatments for MDS and AML. Medicinal chemistry efforts in the teams’ laboratories have led to the discovery of lead compound NCGC-1481, a highly potent inhibitor of IRAK1/4, FLT3, and many of the most common mutant forms of FLT3. In the MA9-FLT3-ITD cancer cell line, which contains a mutant form of FLT3, compounds from this series effectively block compensatory signaling through IRAK1/4. These compounds also block the growth and proliferation of MA9-FLT3-ITD cancer cells. In a mouse xenograft model of AML, NCGC-1481 produced an increase in survival time comparable to that of the Phase II candidate AC220. This is notable, given the fact that NCGC-1481 is not yet a fully optimized compound. Current efforts are aimed at further improving the properties of compounds in this series, with the ultimate goal of advancing an optimized candidate into clinical trials as a treatment for MDS and AML. This figure illustrates the chemical structure of lead compound NCGC-1481. The bar graph in the center indicates the numbers of MA9-FLT3-ITD cancer cells remaining (colony number) after treatment with control (black bar on far left), the Phase II FLT3 inhibitor AC220 (gray bar that is second to left), NCGC-2327 (red bar that is third from the left), or NCGC-1481 (blue bar that is fourth from the left). The line graph on the right indicates the percentage of mice surviving after xenograft transplant upon treatment with control (black line on left), AC220 (red line on the left), or NCGC-1481 (blue line in the middle). Lead Collaborators Craig J. Thomas, Ph.D., NCATS, NIH Scott B. Hoyt, Ph.D., NCATS, NIH Dan Starcyznowski, Ph.D., Cincinnati Children’s Hospital Public Health impact This project provides insight into the effects of dual-acting IRAK/FLT3 inhibitors in cancer cell lines and animal models and may yield an optimized candidate for MDS/AML clinical trials. | Development of Dual-Acting IRAK/FLT3 Inhibitors | Development of Dual-Acting IRAK/FLT3 Inhibitors | ||||||
| 8844 | Chemistry Technology in Action | Find out what chemistry technology experts at NCATS have been working on. The aim of the Chemistry Technology program is to provide advanced tools to help the broader biomedical research community carry out basic and translational studies in a faster, more in-depth manner. To achieve this, we take part in a variety of innovative translational research activities. Read the latest news about these activities. November 2019A Promising Step in the Fight Against Lethal Childhood Brain CancersResearchers have found a promising two-drug combination to treat deadly childhood brain cancers known as diffuse midline gliomas. The drug pair kills cancer cells and counters the effects of a genetic mutation that causes the cancers.September 2019NIH, Cincinnati Children’s Scientists Develop Potential Strategy Against Leukemia Drug ResistanceScientists at NCATS and Cincinnati Children’s Hospital Medical Center have developed a possible treatment for a common type of leukemia that also could be useful for many other types of cancer. The new approach focuses on a way that cancer cells dodge the effects of drugs. | The NCATS Chemistry Technology program provides cutting-edge resources to the broader biomedical research community. Read the latest news about Chemistry Technology program activities. | /sites/default/files/chemtech_dpischolars_1260x630.jpg | Chemistry Technology in Action | The NCATS Chemistry Technology program provides cutting-edge resources to the broader biomedical research community. Read the latest news about Chemistry Technology program activities. | /sites/default/files/chemtech_dpischolars_1260x630.jpg | Chemistry Technology in Action | ||
| 8842 | CTSA Program Fosters Next Generation of Translational Scholars | Translational Science Highlight An NCATS-funded educational program provides trainees with the skills, knowledge and core competencies needed to advance translational science while also fostering a diverse, transdisciplinary workforce. Peter Nagele, M.D., M.Sc., always knew he wanted to be a researcher. If he had attended medical school in the United States, he might have also pursued a Ph.D., which includes significant training in research. But studying in Austria offered few opportunities for physicians to learn how to conduct research. “In Austria, it was understood that during my residency, if you wanted to continue in academia, you should go to the U.S.,” he explained. This understanding led Nagele to Washington University in St. Louis to work in a basic science laboratory, where he studied how anesthesia works. He later became part of the university’s Institute of Clinical and Translational Sciences (ICTS), funded through NCATS’ Clinical and Translational Science Awards (CTSA) Program, an innovative national network of medical research centers working together to improve the translational research process to get more treatments to more patients more quickly. Cultivating the next generation of clinical and translational researchers relies on the availability of robust scientific training and career development programs to disseminate required knowledge, skill sets and core competencies. Offering support to trainees across the country through the CTSA Program is just one way NCATS addresses a national shortage of clinical investigators. The Scientific Workforce of the Future In most academic medical centers, research has historically focused on basic biomedical research in the lab. Physician-scientists who wanted to conduct clinical trials or large population-based studies often had to acquire those skills on their own, according to Vicky Fraser, M.D., director of the KL2 Mentored Career Development Program at Washington University and former director of the ICTS Clinical Research Training Center (CRTC). Anesthesiologist Peter Nagele learned the foundations of clinical and translational research at Washington University’s Clinical Research Training Center. “Now, NCATS has created a more standardized path for training in clinical research, providing the resources and framework to train groups of individuals from diverse disciplines on topics such as study design, research ethics, community-engaged research, statistics and scientific writing.” “We aim to help trainees become proficient in research methodology, regardless of whether they’re in neurology or physical therapy research,” said David Warren, M.D., M.P.H., director of the ICTS CRTC. “We provide many of the necessary tools to be successful clinical and translational researchers.” Nagele became one of the first investigators trained in clinical research at the ICTS CRTC. He took part in its Postdoctoral Mentored Training Program in Clinical Investigation. He also received additional NIH funding through a program that supports career development for investigators who have made a commitment to focus on patient-oriented research. “A lot of people have ideas for studies, but you need to be able to design the study in such a way that it moves the science forward,” he said. “If you make methodological mistakes, no one is going to believe you and no one is going to fund you.” “CRTC offerings are designed to mentor and develop diverse groups of trainees from many different scientific and medical fields, with broad research interests and educational backgrounds,” Fraser said. “We pay attention to diversity of disciplines, gender and ethnicity,” she added. “Having a more diverse and inclusive community fosters excellence, innovation and new ways of thinking.” The Road to Independent Investigator While Ana María Arbeláez, M.D., M.S., was in medical school in Colombia, South America, her community had very high rates of cervical cancer, raising concerns about local risk factors that may have influenced the development of the disease. Without computers, she studied the epidemiology of cervical cancer in the community with two of her classmates, calculating the statistics by hand. Arbeláez followed her interest in academic medicine and research to the University of Miami for her pediatric residency, and then to Washington University for endocrinology training, where she joined Nagele in the first group of ICTS trainees. Ana María Arbeláez, M.D., M.S. Arbeláez began working in a lab that focused on the effects of hypoglycemia, a complication of diabetes triggered by taking too much insulin. After participating in the ICTS Postdoctoral Mentored Training Program in Clinical Investigation, she received CTSA Program KL2 Career Development funding that guarantees young researchers two to three years of protected time to focus on research, including learning how to conduct studies. “Having that protected time makes a big difference,” she explained. “Otherwise, it’s very easy to be pulled in too many directions.” As a non-native English speaker, Arbeláez found the writing classes particularly useful. The network of students from a variety of disciplines and backgrounds also helped. “There were trainees in situations similar to my own and we read each other’s grant applications,” she said. Today, both Nagele and Arbeláez are independent researchers. Nagele is supported through a grant from NIH’s National Heart, Lung, and Blood Institute to test a method for reducing the risk of heart attack, a serious complication after surgery, and by NIH’s National Institute of Mental Health to study the use of nitrous oxide, also known as “laughing gas,” for depression. Arbeláez is studying the effects of hypoglycemia on the brain with a research grant from NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. The Work Pays Off As part of their training, both Arbeláez and Nagele earned a Master of Science in Clinical Investigation. The CRTC also offers a Master of Science in Applied Health Behavior Research and a Master of Population Health Sciences. CRTC program coursework counts toward these degrees. In addition to a research mentor, trainees also have what Warren calls a close “programmatic mentor” — a CRTC director or associate director who is a successful researcher and who helps trainees stay on track with career development. The mentoring continues as trainees take steps toward independence, such as applying for their own grants. Many CRTC alumni, including Arbeláez, become mentors themselves. In addition to chief of pediatric endocrinology, Arbeláez is now director of an additional Washington University pre-doctoral training initiative that NCATS funds through its CTSA Program to provide training in clinical and translational research to students who are working toward an M.D. or Ph.D. “As a physician, you make a difference one patient at a time,” Arbeláez said. “By conducting research, you can have a much broader impact.” Posted January 2018 | CTSA Program Fosters Next Generation of Translational Scholars | CTSA Program Fosters Next Generation of Translational Scholars | ||||||
| 8841 | NCATS-Supported Consortium Charts New Course for Rare Immune Diseases | Translational Science Highlight NCATS-supported research consortium scientists are conducting natural history studies and defining rare genetic diseases. By studying related rare diseases, the research team breaks down translational barriers in sharing knowledge and developing therapies for rare immune system disorders. While in medical school in the early 1970s, Jennifer Puck, M.D., served a medical rotation at the Navajo Nation in Arizona and New Mexico. After her rotation, she subsequently learned that the Navajo had an unusually high incidence of severe combined immunodeficiency (SCID), an inherited disorder that robs the immune system of its ability to fight infections. Decades later, Puck, through the NCATS-supported Primary Immune Deficiency Treatment Consortium (PIDTC), again would work with the Navajo to help change the outlook of the disease. Today, Puck is a pediatric immunology specialist at the University of California, San Francisco (UCSF), where she studies SCID and other rare immune system diseases. At UCSF, she joined the PIDTC, a research collaborative of 45 institutions in the United States and Canada headed by pediatric immunologist Morton Cowan, M.D., and part of NCATS’ Rare Diseases Clinical Research Network (RDCRN). The PIDTC’s work is ushering in a new era of understanding about disorders that can devastate the body’s ability to fend off disease. Cowan, professor emeritus of pediatrics and former chief of the Pediatric Allergy, Immunology and Bone Marrow Transplant Division at UCSF, also has a long-time connection to the Navajo; he has worked with a group in Arizona for more than 25 years and first reported the gene mutation that causes SCID in Athabascan-speaking Native Americans (Navajo and Apache Indians). Cowan is principal investigator of the PIDTC, which focuses on better understanding and developing therapies for three types of rare primary immune deficiencies: SCID, Wiskott-Aldrich syndrome and chronic granulomatous disease. The PIDTC is supported by the RDCRN and NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The RDCRN program supports rare diseases research through clinical studies and facilitating collaboration, study enrollment and data sharing. Scientists from different disciplines at hundreds of clinical sites around the world work together with patient advocacy groups to study more than 280 rare diseases. “RDCRN support has helped overcome critical translational science barriers in better understanding several rare immune disorders,” said Tiina Urv, Ph.D., program director for the RDCRN in the NCATS Office of Rare Diseases Research. “PIDTC researchers are working together on large studies to reveal insights into disease biology, the long-term effects of treatments and the potential for improved therapies.” SCID includes several rare disorders caused by mutations in genes involved in the development and function of immune cells that fight infection. Babies with SCID often die before age two unless they receive gene therapy, enzyme replacement treatment or a hematopoietic stem cell transplant. For nearly 50 years, clinicians have been using transplants — which are designed to help re-establish the recipient’s blood cell-forming abilities and restore the immune system — to treat children with SCID. Based on PIDTC studies, about 60 percent to 70 percent of children who receive stem cell transplants for SCID live at least into their 20s or 30s. Early Screening and Treatment Despite general improvements in patient survival, clinicians treating patients with immune deficiency disorders often used approaches to therapy based on small numbers of patients seen at individual institutions. To make progress, these providers needed a centralized organization to help coordinate research studies, establish collaborations and develop treatment standards. Dr. Mort Cowan sees patient Everett Schmitt, 18 months, and his mother Anne Klein at the University of California, San Francisco (UCSF). Everett was treated at UCSF for severe combined immunodeficiency (SCID) through a bone marrow transplant at seven weeks old, where doctors there developed a newborn screening test for SCID. PIDTC was launched in 2009 to tackle these challenges, and consortium scientists quickly found a translational roadblock in their way: the lack of natural history studies of immune deficiency disorders. These studies help investigators understand how diseases progress over time, how patients have been treated and the effects of those treatments. This information would enable researchers to compare and evaluate therapies and provide a shared foundation for the development of treatment standards. Puck and her colleagues also had another concern: it was difficult to know which babies had SCID until they got sick. Puck had developed a newborn screening test a few years earlier, and she and Cowan subsequently led a PIDTC-funded pilot project and clinical trial to study the effectiveness of large-scale screening of newborns for SCID in the Navajo Nation, where Cowan already held annual SCID clinics. The screening test proved successful and was instrumental in convincing the Navajo Nation to institute screening throughout the reservation. A subsequent study of 11 states using newborn screening for SCID showed the disorder was much more common than previously thought. Rather than an incidence of one case in 100,000 newborns, scientists reported that the figure was closer to one in 58,000. The importance of screening and early detection was quickly evident. In a 2014 New England Journal of Medicine study, Cowan; Puck; NIAID’s Linda Griffith, M.D., Ph.D.; and their PIDTC colleagues demonstrated that newborns who were diagnosed with SCID between 2000 and 2009 and treated with a stem cell transplant within three and a half months of birth tended to fare much better than those receiving a transplant later in life, primarily due to an improved ability to fight infections. Newborn screening for SCID is used in all but two states in the U.S. “We demonstrated how effective transplants for SCID had become and how important it is for patients to be diagnosed and transplanted early,” Puck said. “It really changed people’s view of the disease and what was possible.” Studying long-term health As more children with SCID are living longer with treatment, PIDTC researchers have taken the lead in examining the long-term effects resulting from transplants, such as neurocognitive difficulties, lung disease, and fertility and hearing problems. PIDTC-supported researchers currently are completing a large, retrospective study of the long-term health of nearly 600 SCID patients who have received a stem cell transplant since 1982. Such studies have also revealed more about SCID biology and disease types. The specific genetic form of SCID matters; it affects the disease’s progression and the therapy used. “Previously, we could only look at symptoms and disease effects, which were often based on the levels of certain types of immune system cells, including infection-fighting B and T cells,” Cowan said. “Now we are beginning to put patients in categories based on SCID genetic make-up and how they respond to therapy.” PIDTC investigators currently are recruiting patients for forward-looking prospective trials as well. “We want to find out what patients’ immunity and overall health and lifestyles are like years after treatment,” Cowan said. “We have about 140 surviving patients with SCID after 20 years. Along with European collaborators, we’ll have the largest report of survivors who are living 20 years after their transplant.” In addition, to date, they have enrolled nearly 250 newly diagnosed patients with SCID to study how their immune systems fare after treatment and over time. Other PIDTC-led studies focus on improving the treatment of SCID using gene therapy, in which a specially modified virus delivers a correct copy of a faulty gene to the patient. SCID was the first disease treated with gene therapy, and some patients unexpectedly developed cancer following treatment. PIDTC investigators are also examining the use of the chemotherapy drug busulfan, often used in preparing a patient’s immune system for a stem cell transplant. Researchers are conducting a multicenter prospective trial of newly diagnosed babies to identify the safest, lowest effective dose of the drug. Puck credits the PIDTC with making such research studies possible. “These are rare disorders, and no single institution has enough patients to move the field forward,” she said. “SCID isn’t one disease,” she added. “It involves more than a dozen different genes that we know of and many others we don’t. We’re learning what treatments work best for different types of disease and patients. We continue to ask questions that can change practice and the care of patients, and the consortium is playing an important role in making it happen.” Posted January 2018 | /sites/default/files/rdcrn_1260x630.jpg | NCATS-Supported Consortium Charts New Course for Rare Immune Diseases | /sites/default/files/rdcrn_1260x630.jpg | NCATS-Supported Consortium Charts New Course for Rare Immune Diseases | ||||
| 8836 | Strategic Goal 4: Enhance good stewardship of public funds by promoting and employing efficient and effective management practices. | NCATS is a steward of public resources, and, as such, has the responsibility to deploy those resources in the most effective manner. This requires not only supporting innovative research, but also fostering continuous improvement in its operations to improve scientific stewardship. NCATS will use efficient management practices and will work with its employees, awardees and partners throughout the government and beyond to leverage available resources toward the development and dissemination of medical interventions. | NCATS is a steward of public resources, and, as such, has the responsibility to deploy those resources in the most effective manner. This requires not only supporting innovative research, but also fos | /sites/default/files/strategic-plan_900px.jpg | Strategic Goal 4: Enhancing Stewardship | NCATS is a steward of public resources, and, as such, has the responsibility to deploy those resources in the most effective manner. This requires not only supporting innovative research, but also fos | /sites/default/files/strategic-plan_900px.jpg | Strategic Goal 4: Enhancing Stewardship | ||
| 8835 | Strategic Goal 3: Develop and foster innovative translational training and a highly skilled, creative and diverse translational science workforce. | A key to advancing the burgeoning field of translational science is through development of translational science education and training, and support for a diverse translational science workforce. Translation is inherently cross-disciplinary, and will benefit not only from robust training in one or more scientific research domains, but also from broad-based education on the scientific and operational principles that underlie sound translational science. This type of training will enable team members to be more effective in project planning and management, as they will be able to anticipate the needs and requirements at the next phases of the translational process. To foster an innovative translational science workforce, NCATS will catalyze the development, utilization and dissemination of training concepts and programs in translational science; foster ongoing efforts to support translational science as a discipline; and engage broad audiences about translational science so they may participate in the translational process or pursue a career in translational science. | A key to advancing the burgeoning field of translational science is through development of translational science education and training, and support for a diverse translational science workforce. Tran | /sites/default/files/strategic-plan_900px.jpg | Strategic Goal 3: Developing the Translational Workforce | A key to advancing the burgeoning field of translational science is through development of translational science education and training, and support for a diverse translational science workforce. Tran | /sites/default/files/strategic-plan_900px.jpg | Strategic Goal 3: Developing the Translational Workforce |
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