Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Institute of Neurological Disorders and Stroke (NINDS)

Overview of Rare Diseases Research Activities

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to reduce the burden of neurological disease—a burden borne by every age group and every segment of society worldwide. The brain, spinal cord, and nerves are vulnerable to hundreds of disorders, most of which are rare. Even more common diseases such as stroke, epilepsy, and Parkinson’s disease include rare subtypes. NINDS supports research to uncover the causes of and develop treatments for individual rare disorders, while also promoting cross-cutting research on topics such as stem cells, gene therapy, and neuroimaging that will impact multiple neurological disorders.

NINDS supports basic, clinical, and translational research on rare diseases through both its extramural and intramural programs. NINDS also collaborates with the NIH Office of Rare Diseases (ORD) and rare disease voluntary organizations to stimulate specific research areas via workshops, grant solicitations, and strategic planning efforts. The Institute’s primary support of research is through unsolicited, investigator-initiated grant awards, as investigators often have the greatest insight into the critical questions facing a particular field of research. Of the new grants funded by the NINDS in FY 2004, many focused on rare diseases. Examples include prion diseases, Batten disease, Niemann-Pick C, Huntington’s disease, muscular dystrophy, tuberous sclerosis, Rett syndrome, Fragile X, Joubert syndrome, Hurler syndrome, Tay-Sachs disease, Wilson’s disease, narcolepsy, Lowe syndrome, sickle cell anemia, Williams syndrome, dystonia, neurofibromatosis, neural tube defects, amyotrophic lateral sclerosis, and Friedreich’s ataxia.

Recent Scientific Advances in Rare Diseases Research


Ataxia-Telangiectasia is a severe neurodegenerative disease that affects the brain and other systems in childhood and is caused by mutations in the ATM (A-T mutated) gene. In about 14 percent of cases, the mutation creates a “stop” signal in the gene, which causes the ATM protein to be truncated and therefore become nonfunctional. Researchers now have determined that certain antibiotics (aminoglycosides) allow cultured cells to ignore this stop sign and make full-length and functional ATM protein. Several clinical studies have shown that a relatively small amount of functional ATM protein can be beneficial, so this study using antibiotics is a promising strategy for follow-up in animal studies and possibly for clinical trials in humans.

Fabry Disease

Fabry disease is a hereditary disorder characterized by recurrent episodes of severe pain and other symptoms including skin, heart, eye, and kidney problems. The disease is caused by a faulty enzyme, α-galactosidase, which causes lipids to accumulate in cells to harmful levels. NINDS intramural researchers have made advances toward several therapies for Fabry disease. The FDA has approved an enzyme replacement therapy for Fabry disease based on positive results in NINDS intramural trials. Because enzyme replacement therapy may have limitations for long-term use, intramural researchers are also exploring gene therapy as a potential treatment for Fabry disease. Following up on successful gene therapy experiments in adult mice, researchers recently showed that a single treatment given to newborn Fabry mice with a virus containing the α-galactoside gene resulted in long-term correction of the disease defect without an undesirable immune response. If the therapy can be adapted to humans, it may provide a well-tolerated treatment for the disease at an early stage before irreversible organ damage occurs.

Familial Dysautonomia (hereditary sensory and autonomic neuropathy type III)

Hereditary sensory and autonomic neuropathy type III, also called Riley-Day syndrome or familial dysautonomia, disrupts the brain’s control of bodily systems such as gastrointestinal function, respiration, and the cardiovascular system. In people with this disease, a gene mutation causes cells to leave out a critical segment of the IKBAP protein, leading ultimately to degeneration of nerve cells. Researchers have found that kinetin, a plant growth regulating hormone, significantly increases the production of normal IKBAP protein in blood cells that have the disease-causing gene defect. This drug was found by screening a set of 1,040 FDA-approved candidate compounds in the NINDS Custom Collection developed for screening against models of neurological disorders. The finding that a drug can increase production of normal full-length IKBAP in cells is exciting because even subtle changes in the level of protein can have a drastic effect on the severity of this and other diseases caused by similar defects.

Muscular Dystrophy

Duchenne muscular dystrophy is an inherited disorder that causes progressive degeneration of skeletal muscles, leading to severe disability and, ultimately, death. More than a decade ago, researchers discovered that a genetic mutation leads to lack of a protein called dystrophin, which in turn causes muscle degeneration. Researchers have developed a method to deliver therapeutic genes to skeletal muscles throughout the body of a mouse strain that mimics human Duchenne muscular dystrophy. To carry the corrective gene, a modified version of the dystrophin gene that is smaller but still functional, the investigators used an engineered version of a specific type of virus, which can enter muscle cells and not trigger an immune response. Importantly, the investigators co-injected a blood vessel growth factor that temporarily renders the blood vessels permeable so that the vector can efficiently pass through. The corrective gene was widely expressed throughout the skeletal muscles of the mice, and the dystrophy in the mice was dramatically improved by the procedure.

The investigators are gathering the necessary data to see if this treatment can be safely tried in people, which may still be several years away. Researchers need to know, for example, whether the procedure will work in larger animals and whether it remains safe over longer periods of time. If successful, the strategy might be adapted to carry different genes for treating other muscle diseases, including several other forms of muscular dystrophy, and also to deliver therapeutic genes to heart muscle cells.

Rapid-Onset Dystonia Parkinsonism

Researchers have identified the gene defects responsible for a rare inherited form of dystonia, known as rapid-onset dystonia parkinsonism (RDP), that usually strikes adolescents or young adults. RDP is unusual in that symptoms arise very suddenly, often following emotional or physical stress such as fever, childbirth, or prolonged exposure to heat or exercise. The gene defects lead to abnormalities in a protein that normally pumps potassium and sodium into and out of cells to maintain their proper concentrations when nerve cells are active. One possibility is that the abnormal pump protein cannot keep up in stressful circumstances, triggering disease symptoms. Future studies will determine how mutations in the gene cause susceptibility to RDP and might also provide clues to other forms of dystonia, parkinsonism, or even epilepsy.

Spinal Bulbar Muscular Atrophy

X-linked spinal bulbar muscular atrophy, also called SBMA or Kennedy’s disease, is an inherited disorder that causes motor neurons, the nerve cells that control muscles, to degenerate. The disease affects adult men and causes progressively worsening muscle weakness, cramping, and atrophy, which can also result in problems with speech and swallowing. Scientists have determined a critical link by which the gene mutation in SBMA causes the death of motor neurons. The research team genetically engineered a mouse strain that carries the human mutation and develops symptoms strikingly reminiscent of human SBMA. By studying the mice, the researchers determined that the levels of VEGF, a natural growth-promoting substance, were dramatically reduced in the spinal cord before the onset of symptoms. The reduction of VEGF appeared to result from an interaction between the mutated gene product and a regulator molecule. In a first step toward testing a therapeutic strategy based on this finding, the investigators found that artificially increasing VEGF itself or its regulator rescued motor neuron-like cells in a cell culture model of SBMA. Further experiments are under way in the SBMA mice to test this approach.

Spinocerebellar Ataxia Type I

Spinocerebellar ataxia type 1 (SCA1) is one of many neurodegenerative diseases caused by a dominant inherited mechanism, where a single defective copy of a gene from either parent produces a defective protein that is harmful and causes disease. People with spinocerebellar ataxias experience failure of muscle control in their arms and legs, balance problems, and disturbance of gait, which progressively worsens. Researchers have used a promising new therapy to silence the toxic disease gene in mice genetically engineered to carry the gene defect that causes human SCA1. Researchers developed a modified (and harmless) virus that carries a molecule, called a short hairpin RNA. This molecule is designed to suppress only the defective gene through a process called RNA interference. RNA interference takes advantage of a recently discovered process that cells may have evolved to help protect themselves from viruses. Young SCA1 mice treated with this procedure showed strongly improved movement control and a healthier brain structure than untreated mice. If this approach can be made safe and effective for use in people, this new therapeutic strategy should be applicable to other dominantly inherited neurodegenerative diseases.

New/Planned Research Initiatives

NINDS supported and stimulated research related to rare disease under the following FY 2004 solicitations, some of which were issued in collaboration with other Institutes and patient voluntary organizations:

  • Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers (with NIAMS and NICHD)
  • The Etiology, Pathogenesis, and Treatment of ALS (with Department of Veteran’s Affairs and the Amyotrophic Lateral Sclerosis Association)
  • National Centers for Neurofibromatosis Research (with NIDCD)
  • CNS Therapy Development for Lysosomal Storage Disorders (with NIH ORD and the Lysosomal Storage Disease Research Consortium)
  • The SMA Project: A Collaborative Program to Accelerate Therapeutics Development for Spinal Muscular Atrophy
  • NINDS Pilot Therapeutics Network Clinical Operations Center: NPTUNE COC
  • Announcement of Request for Proposals: Inducible Mouse Models of Spinal Muscular Atrophy (SMA)
  • Novel Approaches to Enhance Animal Stem Cell Research (with multiple NIH Institutes)

Among planned solicitations are:

  • Microarray Centers for Research on the Nervous System (with NIMH)
  • Centers of Excellence in Translational Human Stem Cell Research (with NIDDK and NHLBI)
  • An In Vitro Biological Assay Facility for Screening Compounds in Cellular Models of Spinal Muscular Atrophy (SMA)
  • NIH Administrative Supplements for Senator Paul D. Wellstone Muscular Dystrophy Research Fellowships at Wellstone Muscular Dystrophy Cooperative Research Centers (MDCRCs)
  • Accelerating Therapy Development for Tuberous Sclerosis
  • Basic and Clinical Research on Rett Syndrome and MeCP2
  • Delivery of RNAi Therapeutics into the Nervous System
  • Mechanisms of Transmission and Dissemination of Transmissible Spongiform Encephalopathies

Significant Ongoing Rare Disease Research Activities

A number of NINDS intramural clinical studies begun in FY 2004 are investigating treatments for rare diseases. Intramural researchers are conducting a series of trials on the dosage and effectiveness of Replagal enzyme replacement therapy for Fabry disease. An NINDS pilot study has been initiated to evaluate the effect of direct current electrical polarization of the brain on patients with Pick’s disease. In addition, the drug Rituximab, which has shown promise in treating other antibody-mediated disorders, is being tested for safety, tolerability, and efficacy in patients with stiff person syndrome (SPS). NINDS is also supporting clinical trials through its extramural program for treatment of rare diseases such as amyotrophic lateral sclerosis (ALS), Canavan disease, spinal muscular atrophy (SMA), and Tourette syndrome.

NINDS, together with NIAMS and NICHD, has been actively implementing the provisions of the Muscular Dystrophy Community Assistance, Research, and Education Amendments of 2001 (the “MD-CARE Act”). In 2002, the NIH issued a Request for Applications (RFA) to establish Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers and awarded three grants in October 2003. The NINDS funds a Center at the University of Rochester that focuses on the myotonic and facioscapulohumeral forms of muscular dystrophy. In FY 2004, the NIH reissued the RFA and expects to fund up to three additional meritorious centers. Also in compliance with the MD-CARE Act, the Muscular Dystrophy Coordinating Committee (MDCC), composed of representatives from government agencies with an interest in muscular dystrophy (including NINDS, NIAMS, and NICHD) developed a Muscular Dystrophy Research and Education Plan for NIH, which was submitted to Congress in August 2004. The MDCC met in December 2004 to involve public and private sector partners in the implementation of the plan. These efforts should enhance cooperation among government and patient advocacy groups to utilize the strengths each brings to research and education in muscular dystrophy.

The SMA project is a unique program to develop therapies for SMA. The performance-based contract mechanism accelerates all steps from recognition of a research need, through solicitation, review, and funding of targeted research subprojects. An expert steering committee, with members from academia, industry, the FDA, and the NIH, actively drives the process. In its first year, the SMA Project has moved quickly. The steering committee developed detailed plans for SMA drug development, and planning for gene therapy is under way. The SMA project issued six solicitations for targeted research subprojects, and research has begun. With the ongoing consultation of the steering committee, the contractor will solicit and coordinate individual research projects in areas such as drug development, gene therapy, and stem cell therapy. This contract-based SMA translational program is the first of its kind at NINDS and may eventually serve as a model for other diseases. As a complement to the SMA Project, a workshop in September 2004 engaged the SMA scientific community, clinicians, and voluntary health organizations on development of clinical trials.

In an effort to facilitate the timely translation of promising therapies into clinical trials, NINDS established a pilot clinical trial infrastructure network called the NINDS Pilot Therapeutics Network Clinical Operations Center (NPTUNE COC). A contract has been awarded and a steering committee formed to select candidate therapies for the first pilot trials. Since the NPTUNE project will focus on disease areas with promising interventions that currently lack sufficient infrastructure and/or experience in clinical trials, many of the disease areas under consideration are rare diseases. The first pilot trial under the NPTUNE program will be for SMA. Eventually, the NINDS hopes to run two or more concurrent pilot clinical trials through the network.

Scientific Conferences, Workshops, Symposia, and Meetings

In FY 2004, the NINDS led or participated in the following workshops relevant to rare diseases. In most cases, the Institute collaborated with the NIH ORD or other NIH Institutes and often with patient voluntary groups.

  • Annual Symposium WORLD Lysosomal Diseases Clinical Research Network
  • Calcium and Cell Function
  • Clinical Trials in Spinal Muscular Atrophy
  • Developing Therapies for the Neurofibromatoses
  • First International Conference on Ideomotor Apraxia
  • Fourth International Scientific and Clinical Symposium on Tourette Syndrome
  • Frontotemporal Dementia and Pick’s Disease Satellite Meeting at 9th World Alzheimer’s Congress
  • Glutamic Acid Decarboxylase Autoimmunity in Batten Disease/Juvenile Neuronal Ceroid Lipofuscinosis (JNCL)
  • Hershey Conference on Developmental Brain Injury
  • Overcoming Neurofibromatosis Clinical Research Barriers
  • Pathogenesis of Rare Neuroimmunologic Disorders
  • Primary Lateral Sclerosis (PLS) Diagnostic Criteria Conference
  • The Glycoproteinoses: An International Workshop on Advances in Pathogenesis and Therapy

For FY 2005, the NINDS is working with the NIH ORD on several meetings including workshops focused on drug screening for Ataxia-Telangiectasia, the development of clinical trials for pediatric stroke, and the brain uptake of fatty acids and lipids that relates to lipid storage diseases.


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Last Reviewed: July 22, 2005