Mr. Chairman and Members of the Committee:

I am Audrey Penn, Acting Director of the National Institute of Neurological Disorders and Stroke. I am pleased to present the President's budget request for NINDS for FY2003, a sum of $1,443,392,000, which reflects an increase of $111,744,000 over the comparable Fiscal Year 2002 appropriation. The NIH budget request includes the performance information required by the Government Performance and Results Act (GPRA) of 1993. Prominent in the performance data is NIH's second annual performance report which compared our FY2001 results to the goals in our FY2001 performance plan.

The mission of NINDS is to reduce the burden of neurological disease-a burden borne by every age group, by every segment of society, by people all over the world. The Institute carries out this mission through research on the healthy and diseased brain, spinal cord, and nerves of the body, which together make up our nervous system. The intricacy of the brain is awesome, its workings are elusive, and an extraordinary variety of disorders affect the nervous system. Furthermore, the brain and spinal cord are difficult to access, sensitive to intervention, and reluctant to regenerate following damage. For these reasons, neurological disorders often defy the best efforts of medicine, even in the modern era.

The last decade has brought the first treatments for acute stroke and spinal cord injury, new immune therapies that slow the progression of multiple sclerosis, and increased drug and surgical options for treating Parkinson's disease, epilepsy, and chronic pain. Continuing advances in preventing stroke and birth defects, such as spina bifida, are also improving the public health. Still, treatments for most neurological disorders are far from adequate, often failing to stop or even slow the disease process. What is encouraging, however, is the variety of new treatment and prevention strategies under development: drugs that home in on the molecules that cause disease, stem cell therapies that replace lost nerve cells, neural prostheses that read control signals directly from the brain, vaccines that target neurodegeneration, implantable electronic stimulators that compensate for brain circuits unbalanced by disease, and behavioral interventions that encourage the brain's latent capacity to repair itself.

THE BURDEN OF NEUROLOGICAL DISORDERS

Our strategies are shaped not only by scientific insights but also by the sheer variety of neurological disorders. The causes of neurological disorders include trauma, infections, toxic exposure, developmental defects, degenerative diseases, tumors, gene mutations, systemic illness, vascular events, nutritional deficiencies, immune reactions, and adverse effects of essential treatments, such as cancer chemotherapy. Stroke, chronic pain conditions, dementia, and traumatic brain injury are among the leading causes of death and disability in the nation. Epilepsy, spinal cord injuries, multiple sclerosis, Parkinson's disease, the muscular dystrophies, autism, cerebral palsy, and peripheral nerve disorders, are common enough to be familiar to most Americans. But there are many other neurological disorders unfamiliar to most people until a family member is affected, and Congress has been active in bringing attention to less familiar diseases, including amyotrophic lateral sclerosis (Lou Gehrig's disease), Batten disease, the dystonias, facioscapulohumeral and congenital muscular dystrophies, Friedreich's ataxia, mitochondrial disorders, mucolipidosis type 4, neurofibromatosis, reflex sympathetic dystrophy, spinal muscular atrophy, spina bifida, and tuberous sclerosis. A complete list of neurological disorders would include hundreds more.

DIFFERENT DISEASES, COMMON THEMES

As scientists unravel the complex processes that underlie neurological disorders, ranging from acute stroke to the inexorable chronicity of Parkinson's disease, common themes are emerging, leading to the hope that similar therapeutic and preventive strategies will also apply. To put it another way, progress against a single disease is likely to have a bearing on many others. A few examples of cross-cutting research areas illustrate the broader trend.

Scientists have implicated "free radicals" as culprits in brain damage from stroke and trauma, as well as neurodegenerative diseases like ALS, Parkinson's and Alzheimer's, and even infections that affect the brain. Free radicals are highly reactive chemicals that are normal byproducts of energy metabolism, but can damage cells if produced in excess or improperly controlled. This year scientists discovered that patients with a type of inherited ataxia, a movement disorder, had abnormal levels of a vitamin-like substance called coenzyme Q10, which helps protects cells from free radicals. When researchers provided coenzyme Q10 supplements, the patients responded with improved coordination, increased strength and less frequent seizures. Another research team demonstrated in a clinical trial that the drug allopurinol, chosen to help scavenge free radicals, helps protect the brains of high-risk infants undergoing heart surgery. Several other disease mechanisms repeatedly come into play in many disorders, including excitotoxicity from excessive release of normal brain signaling chemicals, abnormal calcium handling within cells, aggregation of proteins, and activation of "cell suicide" programs. Each of these provides targets for developing preventive and therapeutic strategies that may be widely applicable.

Just as common disease mechanisms help us confront the staggering variety of neurological disorders, there are therapeutic strategies that may apply to many diseases. Gene therapy is deceptively simple in concept, but difficult in practice. The complexities of working with nerve and muscle cells compound the problems. However, scientists have shown promising results in fixing or replacing defective genes in animal models of inherited disorders such as Duchenne muscular dystrophy, and research is demonstrating the potential of gene therapy even in non-inherited disorders, for example, by coaxing cells to make the nerve cell survival factor GDNF or the neurotransmitter dopamine in animals with Parkinson's-like disorders. Stem cells likewise present broad promise. For many years NINDS has supported pioneering research on animal and adult human stem cells, including therapeutic studies in animal models of stroke, spinal cord injury, Parkinson's disease, muscular dystrophy, and inherited metabolic disorders. In the past year, we have seen blood-derived cells convert into nerve-like cells, neural progenitor cells harvested from human brain tissue after death, and stem cells persuaded to become dopamine-secreting nerve cells needed in Parkinson's disease or insulin-secreting cells lacking in diabetes. We are intensifying research on all types of stem cells, as we initiate the study of human embryonic stem cells in accordance with the President's policy announced last August.

Stem cells and gene therapy may have captured the public's attention, but other therapeutic approaches are also promising. Deep brain stimulation (DBS) with implanted electrodes has helped some people with essential tremor and Parkinson's disease and may be more widely applicable to epilepsy, dystonia, pain, and depression. NINDS is building on the expertise of its neural prosthesis program, which helped develop the technology necessary for DBS over the last 30 years, to improve DBS. The Institute is also expanding its drug development efforts to capitalize on the growing understanding of disease at the molecular level. These efforts include high-throughput screening and testing of drugs approved by the FDA for other purposes.

The remarkable progress in understanding the fundamental biology of the brain, of course, is the foundation supporting studies of the common mechanisms of disease and the development of new preventive and therapeutic strategies. Genetics provides one unifying theme, often revealing the first clues to disease processes and yielding animal models for studying disease and testing treatments. The burgeoning research on brain plasticity-how the brain adapts to experience and the environment-may teach us how to encourage adaptive plasticity to foster recovery from stroke and trauma, and also how maladaptive plasticity contributes to chronic pain and dystonia.

PLANNING AND ENABLING RESEARCH

Motivated by scientific opportunity, enabled by budget increases, and guided by strategic and disease specific planning efforts, NINDS is taking a more active role in directing research. The NINDS strategic planning process began in 1998 and drew upon the nations' leading scientists and physicians, the public and Institute staff. The effort coalesced around cross-cutting themes of neuroscience and resulted in the NINDS Strategic Plan: Neuroscience at the New Millenium which has provided a framework for the Institute's activities. These include intensified efforts, through workshops, grant and contract solicitations, and other means as appropriate, that target gene discovery, gene therapy, microarray technology, drug screening, stem cells, deep brain stimulation, pediatric neurology, and common mechanisms of disease, such as mitochondrial dysfunction and protein aggregation.

As NINDS testified last year, the strategic planning process also engendered an increased emphasis on clinical trials, prompted by the opportunities arising from neuroscience research and building on extensive NINDS experience in clinical trials for stroke and other diseases. Ongoing trials range from pilot studies to large phase III efforts, focus on prevention and on treatment, and test interventions that run the gamut, including drugs, surgery, gene therapy, deep brain stimulation, hormone therapy, tissue transplantation, hypothermia, transcranial magnetic stimulation, radiosurgery, behavior modification, and diet, as well as rehabilitation methods. A partial list of disorders being addressed in trials includes: AIDS, ALS, brain tumors, cerebral palsy, attention deficit hyperactivity disorder, brain trauma, epilepsy, Turner syndrome, Parkinson's disease, Lyme disease, migraine, sleep disorders, dystonia,, hereditary ataxias, multiple sclerosis, pain, and stroke. Clinical trial results published during the past year report effective immunotherapy for the symptoms of stiff person syndrome - a rare movement disorder; successful field delivery of emergency care for seizures; clinical benefit of enzyme therapy for Fabry disease; improved management of chronic tension headache with added behavior modification; information regarding estrogen hormone-replacement therapy for women for secondary stroke prevention; and improvements in preventing stroke. To complement the clinical trials program, NINDS is developing a comprehensive program to expedite translational research. Translational research bridges from fundamental discoveries about the brain and disease, and rapidly accumulating results in animal models of diseases such as muscular dystrophy, ataxias, ALS, Alzheimer's, Parkinson's, Huntington's, and many others, to the identification of specific agents to be examined in clinical trials of safety and effectiveness.

NINDS health disparities and disease-specific planning efforts build on the foundation of the strategic planning process. The NINDS is implementing research priorities in stroke, neuroAIDS, epilepsy, pain, and cognitive and emotional health in minorities, and in infrastructure and partnership development in minority institutions. NIH has reported separately to Congress, as directed, about progress in implementing the Parkinson's Disease Research Agenda and the January 2002 Consortium meeting. The Agenda represents the most concerted attack NINDS has undertaken against any disease, from basic studies of brain mechanisms through large clinical trials, including efforts to refine existing therapies and to develop new strategies on the frontiers of medicine, such as stem cells, deep brain stimulation, and gene therapy. Among the many facets of this program, the Institute is embarking on a large clinical trial to test drugs that actually slow the course of the disease, rather than merely lessening symptoms.

Other disease-specific planning and implementation efforts are, or will soon be, underway. In March 2000, a landmark conference, "Curing Epilepsy: Focus on the Future," began a process through which epilepsy researchers, patient advocates, and NINDS staff formulated "benchmarks" for epilepsy research, and developed a process to engage the entire epilepsy research community in attaining those goals. NINDS has also reported separately to Congress on this effort, as requested. Major NINDS planning efforts in brain tumor and stroke are following the Progress Review Group (or PRG) model developed by the National Cancer Institute; the brain tumor effort in direct collaboration with NCI. In each PRG, more than 100 scientists and representatives of voluntary groups assess the current state of the science and identify future needs and opportunities. The Institute is also undertaking planning efforts in muscular dystrophy and tuberous sclerosis research in the coming year. NINDS is coordinating NIH efforts to implement the DHHS Bovine Spongiform Encephalopathy (BSE)/ Transmissible Spongiform Encephalopathy (TSE) Action Plan. BSE, known ass "mad cow" disease, is one of the TSEs that pose a potential threat to the public health and economy, and the HHS plan includes surveillance, protection, research and oversight activities. It is important to emphasize that NINDS is also continuing to hold workshops focused on a wide range of specific disorders, such as dystonia, congenital muscular dystrophy, familial dysautonomia, pediatric neurotransmitter diseases, and Joubert syndrome. These meetings, and the ongoing informal interaction among NINDS professional staff, the research community, and disease advocates, catalyze research, while informing the Institute where specific solicitations or other actions may be warranted. Finally, unsolicited grants continue to be the backbone of NINDS research efforts. The collective wisdom of scientists and physicians throughout the nation is especially suited to confronting the broad spectrum of neurological disorders and the scope of science that is essential to progress.

In conclusion, it would be a disservice to patients and families to promise when cures will become available, because medical progress is notoriously difficult to predict. Yet researchers are cautiously optimistic that, by recognizing cross-cutting areas of scientific opportunity, while maintaining a continuing focus on the unique aspects of each disease, we are moving toward an era when curing or preventing neurological disorders will become commonplace. Thank you.

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