Story C. Landis, Ph.D., Director
National Institute of Neurological Disorders and Stroke
March 24, 2010
Mr. Chairman and Members of the Committee:
The mission of the NINDS is to reduce the burden of neurological disorders through research. NINDS-funded research has prevented thousands of strokes, improved treatments for stroke, epilepsy, multiple sclerosis, Parkinson’s, and other diseases, and reduced long diagnostic delays for families confronting many rare brain diseases. However, diagnosis, prevention, and treatment are still far from optimal, and many neurological disorders will become more common as our population ages unless we can prevent them. Fortunately, the opportunities that the NIH Director noted for medical science at large are also enabling progress against neurological disorders.
PREVENTION AND COMPARATIVE EFFECTIVENESS RESEARCH
Stroke is the third leading cause of death in the United States and a major cause of long-term disability, but the burden on the health care system would be even greater were it not for the remarkable progress in stroke prevention. U.S. Centers for Disease Control and Prevention statistics show that the stroke death rate, adjusted for age, decreased by 33.5% from 1996 to 2006, and actual stroke deaths declined by 18.4%. NINDS clinical trials are contributing to this progress. Last month, the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) provided risk-benefit information to guide patients and physicians in choosing between two surgical procedures to prevent stroke. For people with certain risk factors, the less invasive stent procedure may be worth considering. NINDS will fund a study to compare the durability of the two procedures. Among other large trials, the Systolic Blood Pressure Intervention Trial (SPRINT), in cooperation with NHLBI, NIDDK and NIA, is testing whether maintaining blood pressure lower than current recommendations further reduces the risk of stroke and other diseases; and the Platelet-Oriented Inhibition in New TIA (POINT) trial will determine whether use of the drug clopridogrel is an improvement over current standard care in preventing major strokes that often follow a transient ischemic attack (TIA), or mini-stroke. POINT alone could save a half billion dollars each year in health care costs if it meets its target for risk reduction.
GENOMICS AND OTHER TECHNOLOGIES
For rare neurological disorders, research over the last two decades has identified hundreds of single gene defects that cause disease. For many disorders, gene identification led to diagnostics, animal models that mimic the human disease, and biological insights. For several diseases, therapies are moving from animal models towards human trials, potentially even reversing developmental disorders, such as Rett and Fragile X syndrome. However, the path from gene discovery to treatments is too slow, especially for diseases like Huntington’s disease and Duchenne muscular dystrophy for which gene defects were discovered two decades ago. This underscores the need for better ways to move from gene discovery to treatment.
NINDS is also investing aggressively to identify genes that influence susceptibility to common disorders, including stroke, epilepsy, multiple sclerosis, and autism, which is now feasible through Genome Wide Association Studies, and new methods such as whole exome sequencing. Parkinson’s disease illustrates the potential. By the time this disease is diagnosed, most nerve cells are already dead in the substantia nigra, the most affected region of the brain. Earlier diagnosis is thus essential for successful intervention. Furthermore, drugs hide symptoms so well as Parkinson’s disease advances that clinical trials take seven or more years to tell whether a drug is actually slowing disease progression. Hence, NIH, industry, disease advocates, and academic researchers agree that the lack of quantitative indicators –that is, biomarkers– of early disease and of disease progression is the critical barrier for development of therapies.
Genomics, proteomics, and other high throughput technologies, as well as brain imaging, behavioral measures, and other methods, are providing many opportunities to develop biomarkers. In genetics, an NINDS workshop led to the first identification of a gene defect responsible for a familial type of Parkinson’s disease. The affected protein, synuclein, was then implicated in common Parkinson’s disease, energizing research on underlying biology. Research has now identified a number of genes that influence Parkinson’s. Each gene gives clues to the biology of the disease, potentially leading to new strategies for diagnosis, treatment, and prevention. Some genes are especially useful for developing and validating early biomarkers because they identify people who have no symptoms but are at high risk for developing the disease.
Induced pluripotent stem cells (iPSc’s) present another opportunity to expedite progress. Based on what researchers learned from embryonic stem cells, they can generate iPSc’s from adult skin cells. With appropriate chemical signals, iPSc’s multiply or form specialized cell types. NINDS is supporting teams of scientists to develop iPSc’s, first from people with inherited Parkinson’s, ALS, Huntington’s, epilepsy, and other diseases, and then for non-inherited diseases. Using iPSc’s from patients to generate the specific cell types affected by each disease could speed high throughput drug screening and other translational studies, as well as basic studies of disease biology and transplant therapies. The NIH IPSc Center funded by the Director’s Common Fund will support research on this emerging opportunity.
TRANSLATING DISCOVERIES INTO BETTER TREATMENTS
For decades, NINDS investments have translated discoveries into treatments – drugs for epilepsy, pioneering neural prosthetics, the first enzyme therapies for inherited disorders, and the first emergency stroke treatment. Responding to increasing opportunities for translation, in 2003 NINDS established the Cooperative Program for Translational Research, with management tailored for preclinical therapy development, including milestone-gated funding. This year the first therapy from this program, a gene therapy for Batten disease, is entering a Phase II clinical trial. In 2009, the NINDS further strengthened its commitment to translational research by establishing an Office of Translational Research (OTR) and recruiting an Associate Director for Translational Research with extensive experience in therapy development. Among notable OTR programs, the SMA (spinal muscular atrophy) Project is a “virtual pharma” drug development program that is on a path to bring a drug to clinical trials by 2011. Other OTR initiatives empower scientists to do preparatory studies that enable them to take full advantage of the NIH Roadmap high throughput screening centers. For 2011, OTR is leading an ambitious collaboration with 15 other NIH Institutes and Centers of the NIH Blueprint for Neuroscience to develop novel drugs that could transform the treatment of neurological, psychiatric, and other nervous system diseases.
To expedite the next steps in developing treatments, the NINDS Office of Clinical Research is creating NINDS-NET, which is a multi-site network to move therapies from preclinical studies into phase II clinical trials. As more candidate therapies emerge, phase II trials will be essential to select the most promising for expensive phase III trials. This network will reduce start-up time, speed enrollment, and lower costs. NINDS-NET is especially important for rare disorders, where infrastructure is often lacking, because supporting separate clinical networks for each of the hundreds of rare neurological diseases is not an efficient use of resources.
Epilepsy illustrates how the NIH-wide themes come together for a specific disease. Epilepsy affects about one percent of the U.S. population. For perhaps one third of these people, treatments are ineffective. Side effects of therapy and problems that accompany seizures, including learning disabilities and psychiatric problems, also seriously affect quality of life, care costs, and economic productivity. For health care reform, the salient fact is that epilepsy imposes an enormous burden on the health care system, which better treatment and prevention would reduce. As one example of recent progress, a clinical trial published this month compared the effectiveness and side effects of three widely used drugs for childhood absence epilepsy, enabling physicians to choose better among treatments for this common disorder. Genomics has already had a major impact on epilepsy research, and NINDS is increasing investments in genomics, iPSc’s, and other enabling technologies for epilepsy. The knowledge gained is leading the way to a new paradigm in which attacking the root causes of epilepsy rather than just suppressing seizures is now a realistic goal. Demonstrating the critical importance of translational research, the NINDS Anticonvulsant Screening Program has contributed to the development of a number of epilepsy drugs that are now in use. A new initiative based on the NINDS milestone-driven translational program will focus on the major unmet needs for interventions against treatment-resistant epilepsy and to prevent the development of epilepsy, which can follow traumatic brain injury, stroke, and other diseases, as well as gene defects. Two additional NINDS epilepsy initiatives reflect NIH-wide efforts to reinvigorate and empower the research community, in this case toward the goal of curing epilepsy. One initiative will support the best teams of investigators, regardless of geography, to attack a key problem in epilepsy through Epilepsy Centers Without Walls. SUDEP (Sudden Unexplained Death in Epilepsy), a devastating and poorly understood problem, is one potential focus. This year researchers provided the first evidence of a biological cause for SUDEP, and cracking this problem clearly will require an interdisciplinary team. Another NINDS initiative builds on lessons learned from the Exceptional Unconventional Research Enabling Knowledge Acceleration (EUREKA) Program. This NIH program, which NIGMS pioneered with NINDS collaboration, uses applications and review procedures that encourage truly innovative research. Finally, for epilepsy and other diseases, several areas of basic neuroscience, including brain development and plasticity, are providing insights that drive progress toward cures. As NINDS targets initiatives to disease specific needs and opportunities, the Institute must sustain vigorous, investigator-initiated basic research, which has profound and unexpected impacts on understanding diseases and developing therapies. Similarly, the Institute must ensure that that the next generation of researchers can establish productive, independent careers confronting the challenges of neuroscience and neurological disorders.
Department of Health and Human Services National Institutes of Health National Institute of Neurological Disorders and Stroke
Story C. Landis, Ph.D.
Dr. Story C. Landis began her appointment as the Director of the National Institute of Neurological Disorders and Stroke (NINDS) on September 1, 2003. A native of New England, Dr. Landis was awarded her B.A. degree in Biology, with highest honors, from Wellesley College (1967), and her M.A. (1970) and Ph.D. (1973) degrees from Harvard University. After postdoctoral work at Harvard University studying transmitter plasticity in sympathetic neurons, she served on the faculty of the Harvard Medical School’s Department of Neurobiology.
In 1985, Dr. Landis joined the faculty of the Case Western Reserve University School (CWRU) of Medicine in Cleveland, Ohio, where she held many academic positions, including Associate Professor of Pharmacology, Professor and Director of the Center on Neurosciences, and Professor and Chairman of the Department of Neurosciences, a department that she was instrumental in establishing. Under her leadership, the CWRU Department of Neurosciences achieved worldwide acclaim and a reputation for excellence. In 1995, Dr. Landis was appointed as the NINDS Scientific Director, and was responsible for the direction and re-engineering of the Institute’s intramural research program. Beginning in 1999, in conjunction with the leadership of the National Institute of Mental Health (NIMH), she spearheaded a movement to bring a sense of unity and common purpose to the numerous laboratories, in multiple NIH Institutes, that conduct leading edge clinical and basic neuroscience research, which has increased research cooperation and collaboration, and has resulted in the construction of the new NIH Neuroscience Research Center, Phase I of which has opened on the NIH campus. Since early 2007, Dr. Landis has also been Chair of the NIH Stem Cell Task Force.
Throughout her research career, Dr. Landis has made many fundamental contributions to understanding the developmental interactions required for synapse formation, and has garnered many honors and awards. Dr. Landis is an elected Fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science, and an elected member of the American Neurological Association. In 2002, she was elected President of the Society for Neuroscience, and served as President-elect until her appointment as the NINDS Director in September 2003. In 2009, Dr. Landis was elected to the Institute of Medicine of the National Academy of Sciences.