Story C. Landis, Ph.D., Director
National Institute of Neurological Disorders and Stroke
May 20, 2010
Mr. Chairman and Members of the Committee:
The important and challenging mission of NINDS is to reduce the burden of neurological disorders through research. Hundreds of disorders of the brain, spinal cord, and the nerves of the body affect people of all ages. Collectively, they cause an enormous burden in lost life, disability, and suffering, and cost billions of dollars each year in medical expenses and reduced productivity. The causes of nervous system disorders are diverse; among them are physical forces of traumatic brain injury, slow degeneration of nerve cells in Parkinson’s and Alzheimer’s disease, gene mutations in brain tumors and inherited diseases, blood vessel block or bleeding in stroke, and toxic effects of treatments for cancer, HIV/AIDS, and other diseases. Compounding the challenge, the brain and spinal cord are intricate in structure, difficult to access, sensitive to intervention, and do not readily repair themselves following damage.
PLANNING FOR THE FUTURE
Over the last two years, NINDS has engaged the scientific community and the public in strategic planning to meet these challenges. Planning took a “blue sky” look at the future, but also gave outside experts unprecedented access to data about NINDS programs to inform recommendations of practical steps to better carry out our mission. Even as we finalize the strategic plan and seek further public input, we are implementing recommendations. One major lesson from planning is the importance of program evaluation; based on the results we are reallocating resources to maximize public health impact. Perhaps the most important message for today, however, is not at the level of program details, but about where we stand with respect to the NINDS mission—treatments for neurological disorders are still far from adequate, but research is yielding remarkable progress, and the prospects for the future are very encouraging.
Stroke, the “S” in NINDS, shows how far we have come and how far we have to go. Stroke remains the third leading cause of death in the United States and a major cause of long term disability. However, American Heart Association statistics show that the age-adjusted stroke death rate decreased by 29.7% from 1995 to 2005, and actual stroke deaths declined by 13.5%, resulting in thousands of lives saved. Many NIH research studies contributed to the decline by predicting who is at risk for stroke, who will do best on which drug, and whether surgery to clean a carotid artery or repair an aneurysm is worth the risk for a particular patient. Research on stroke prevention is continuing apace, including research on the geographic and racial disparities.
About a decade ago, an NINDS clinical trial demonstrated that appropriate use of the clot buster tPA can restore blood flow to the brain and significantly improve outcome from stroke. New clinical trials are building on this first successful emergency treatment by testing whether ultrasound improves tPA’s effectiveness to break up clots in large brain arteries and whether direct injection of tPA into a blocked brain artery or clot retrieval devices may help some patients. Despite its proven benefit, too few people now receive tPA, which must be administered after specialist assessment and within a few hours of a stroke. A trial this year showed that telemedicine can expand access to emergency stroke treatment to areas of the country without specialized stroke centers. A second trial is assessing whether emergency personnel in the field can rapidly deliver a therapy to protect the brain prior to reaching a hospital. Beyond prevention and emergency treatment, a major challenge for stroke, as for traumatic brain injury, is promoting recovery after brain damage has occurred. Rehabilitation that harnesses the brain’s “plasticity” is showing promise in people, and trials are assessing the most effective strategies, but there is still a long way to go.
GENES AND BRAIN DISEASES
Although there are hundreds of neurological disorders, common themes unify research across diseases. One lesson of planning is the importance of engaging the insight and ingenuity of researchers throughout the U.S. to recognize shared disease mechanisms and common therapeutic strategies. Research on genes is one unifying theme that spans many areas of basic and clinical science.
A first wave of progress identified single gene defects that cause more than 200 neurological disorders, and continues with new findings in inherited types of ALS and other diseases. Often, the most immediate benefit of gene findings is genetic tests, which can spare families expensive and frustrating diagnostic odysseys to find out what is wrong with their child. Even when a single gene defect is identified, major obstacles confront therapy to correct the defect, especially in the brain, but there is progress; this year, for example, a preliminary clinical trial established the feasibility of gene transfer to treat Batten disease. Genes can also provide the first foothold on understanding causes and developing drug treatments, leading to rational therapy development programs, as NINDS has underway for muscular dystrophy, spinal muscular atrophy, and other disorders. Although most brain tumors are not inherited, acquired gene defects drive tumor formation. Observing which genes are affected in glioblastoma and other brain tumors is suggesting which tumors respond to which cancer drugs and providing clues to developing more effective treatment.
Recently, scientists have begun to crack the more complex ways that variations in multiple genes together contribute to common neurological disorders and shape individual differences in therapy response. Gene tests show promise for establishing the appropriate dose of the drug warfarin, which is commonly used to prevent stroke in people with certain risk factors. Warfarin now requires frequent blood tests to find the safe and effective dose because of variability among people, and people are at risk until the dose is set. Genome Wide Association Studies, or GWAS, are one method that has associated genes with multiple sclerosis, Parkinson’s disease, stroke, and other common disorders. For example, understanding autism is an NIH-wide priority, and GWAS recently implicated molecules that have been studied in the development of connections among nerve cells, linking a dynamic area of basic research to this disease.
TRANSLATING SCIENTIFIC INSIGHTS TO THERAPIES
NINDS basic and clinical research yield understanding of disease and clinical tools that are essential for therapy development in the private sector. The institute has also long pursued translational opportunities that are not likely to be targeted by others, whether because bold therapeutic strategies present uncertainty and long development horizons that are not tolerable to investors, rare diseases represent a small market, or developments in surgery and interventions using existing drugs may not recapture investments. The NINDS Intramural program developed the first successful enzyme therapy for inherited disease. Among applied NINDS extramural programs, the Anticonvulsant Screening Program has catalyzed the development of several epilepsy drugs now on the market, and the Neural Prosthesis Program successfully pioneered devices to restore lost nervous system functions. In 2003, NINDS moved from selective translational research in a few areas, to a broad effort to capitalize on opportunities across all neurological disorders by initiating the Cooperative Program in Translational Research. This program supports academic and small business investigator-initiated preclinical therapy development, using milestone driven funding and peer review expertise and criteria tailored to therapy development. Therapies from this program have received investigational approval from the FDA and are moving to clinical trials. Based on the advice of strategic planning advisory panels, which included industry experts, NINDS has created an Office of Translational Research and recruited a leader who has extensive drug development expertise. The new office will coordinate and focus NINDS applied programs more effectively on therapy development, without reducing NINDS commitment to basic and clinical research that is the foundation for progress. As new opportunities for therapy development emerge, we cannot let them languish in the “valley of death” between the idea and the success.
Progress against two gene disorders that cause nervous system tumors illustrates how basic understanding of disease can drive research toward treatment. In people who have neurofibromatosis type 1, tumors grow within nerves and can cause disabling symptoms by compressing nerve, spinal cord, and other organs. Several years ago NIH-funded investigators discovered gene mutations that cause the disease and developed animal models that mimic the human disorder. After years of work, researchers discovered how the mutant gene causes cells associated with nerves to develop tumors, and then recruit other cell types and blood vessels to the tumor. Once researchers understood the molecular steps, they recognized that the cancer drug Gleevec acts on the same molecules. They are now testing the drug in people who have neurofibromatosis.
Tuberous sclerosis complex is another disorder in which tumors, called tubers, can grow in nearly any tissue, including the brain. Many people with this disease also develop epilepsy or autism. Again, finding genes led to understanding of the molecular steps in disease, and scientists recognized that an available drug, rapamycin, which is used to prevent organ transplant rejection, affects a key molecule in the disease process. Studies in mice that mimic the human disorder were especially encouraging because the results suggest that the disease can be reversed in adults, countering pessimism that the disease produced irreversible affects on brain development. Researchers are exploring whether rapamycin or similar drugs are safe for long term use, and may also be of benefit for epilepsy or autism from other causes.
THE RESEARCH WORKFORCE
As science progresses, we recognize themes that bring together research on disparate diseases, whether shared disease mechanisms, as in neurodegeneration, therapeutic approaches, as stem cells, or program needs, as translational research. The American Recovery and Reinvestment Act reminds us of another common themeresearch is labor intensive. Progress depends on the men and women who do research and their commitment to research that may take decades. To maintain the vigor of NIH and private research, NINDS is committed to making research an attractive and sustainable career for young people who are innovative, intelligent, dedicated and diverse.