STATEMENT OF
AUDREY S. PENN, M.D.
ACTING DIRECTOR
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

BEFORE THE
SENATE APPROPRIATIONS SUBCOMMITTEE
ON LABOR, HEALTH AND HUMAN SERVICES, EDUCATION AND RELATED AGENCIES

FEBRUARY 27, 2001

Mr. Chairman, Ranking Member Senator Harkin, and Members of the Subcommittee, I am Dr. Audrey Penn, Acting Director of the National Institute of Neurological Disorders and Stroke. I am here to discuss with you the muscular dystrophies. I have been actively involved with this group of diseases throughout my career as a physician and scientist, working in academia, with voluntary organizations, and at the National Institutes of Health.

What are muscular dystrophies?

The muscular dystrophies are a group of diseases which weaken the skeletal muscles that we use to move voluntarily. These disorders vary in their age of onset, in severity and in the pattern of which muscles are affected. All forms of muscular dystrophy, however, grow worse as muscles progressively degenerate. In some types of muscular dystrophy, the heart, the gastrointestinal system, endocrine glands, the skin, the eyes and other organs may be affected. All of the muscular dystrophies are genetic disorders, although the types of inheritance vary, and Duchenne muscular dystrophy, the most common and best known of the childhood muscular dystrophies, often arises from new mutations.

Can we treat muscular dystrophies?

Research has revealed most-but not yet all-of the gene defects that cause the different forms of muscular dystrophy. Unfortunately, the life expectancy and quality of life for people with muscular dystrophy have not improved substantially since those discoveries. There is still no specific treatment that can stop or reverse the progression of any form of muscular dystrophy. For Duchenne muscular dystrophy, corticosteroids may help, but have side effects that can be especially troubling with children. Symptomatic treatment, though not able to stop the disease process, may improve the quality of life for some people with muscular dystrophies, through physical therapy, wheelchairs and braces used for support, corrective orthopedic surgery, and drugs.

The failure so far to produce a definitive therapy for any form of muscular dystrophy reflects the difficulty of the problems that we must confront to cure these diseases. Some of these problems are unique to a particular type of muscular dystrophy, some common to all muscular dystrophies, and others are shared by many genetic disorders. The National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) lead efforts of several components of NIH against these diseases. The shared responsibility recognizes the value that various medical specialties and disciplines bring to research and treatment. The muscular dystrophies affect many aspects of physiology, benefit from a wide range of fundamental biological research, and require exploration of diverse diverse strategies for treatment. What is most encouraging is the range of scientific approaches that research is bringing to bear on these diseases. Molecular biology has given us a foothold to understand what goes wrong. To examine the list of therapies being explored for the muscular dystrophies is tantamount to taking a tour through the most active frontiers of modern medicine, including gene therapy, cell replacement, and innovative approaches to drug development.

Time will not allow me to describe all forms of muscular dystrophy. I will discuss three common types-myotonic muscular dystrophy, fascioscapulohumeral (FSH) muscular dystrophy and Duchenne/Becker muscular dystrophy- and try to make some general points along the way.

Myotonic muscular dystrophy

Myotonic muscular dystrophy (MMD) is probably the most common adult form of muscular dystrophy, partly because people with this disorder can live a long life, with variable but slowly progressive disability. Myotonia refers to impaired muscle relaxation which is associated with MMD along with muscle wasting and weakness. This form of muscular dystrophy affects many body systems in addition to skeletal muscles. These include the heart, endocrine organs, eyes, and gastrointestinal tract.

Myotonic muscular dystrophy follows an autosomal dominant pattern of inheritance. This means that the disorder can occur in either sex when a person inherits a single defective gene from either parent. The gene defect that causes MMD is a triplet repeat expansion in the untranslated region of a gene that encodes a protein kinase (DM-PK). To attempt to translate this into English: the inherited gene defect arises from a long repetition of a three-letter "word" in the part of the genetic code that carries the instructions for making a protein. The protein is one of a class called "kinases" that help regulate the function of other proteins. In this case the "word" is not in the part of the gene that specifies the makeup of the protein itself, but in a region that may help control when the gene is turned on and off. We don't yet understand how this genetic defect leads to muscle degeneration, but the "triplet repeat" mechanism has now been found in at least 15 other disorders. Scientists have found some clues, both for myotonic dystrophy and triplet repeat disorders in general, and research is continuing. The fact that the repetition in the genetic code tends to get longer with each generation explains the phenomenon of "anticipation" in which the disease shows itself earlier and more severely in each generation.

Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) initially affects muscles of the face (facio), shoulders (scapulo), and upper arms (humeral) with progressive weakness. Symptoms usually develop in the teenage years. Life expectancy is normal, but some affected individuals become severely disabled. The pattern of inheritance is, like myotonic muscular dystrophy, autosomal dominant, but the underlying genetic defect is poorly understood. Most cases are associated with a deletion-that is, a missing piece of chromosome-near the end of chromosome #4. These deletions don't appear to disrupt a particular gene, but may affect the activity of nearby genes. This complicates the search for the relevant gene and suggests a novel mechanism may be involved.

In recent months, NIAMS has led NIH in a number of important steps to stimulate and support further work on this poorly understood form of muscular dystrophy. These include:

Research conference: In May 8-9 of 2000, the NIAMS, together with the NINDS, the NIH Office of Rare Diseases, the FSH Society, Inc., and the Muscular Dystrophy Association of America, co-sponsored a scientific conference on the cause and treatment of FSHD. Researchers from the United States, Canada, Europe, South America, and Asia met on the NIH campus in Bethesda, Maryland, to share their latest findings and identify exciting directions for future studies of this disease. The recommendations that emerged from the conference fall into several categories, including: efforts to enhance our understanding of the molecular processes and tissue changes associated with FSHD; ways to explore possible therapies to treat the disorder; and strategies to promote the establishment of population-based studies of the disease, as well as needed research resources. NIH is using these recommendations as a guide in developing new program initiatives related to FSHD and other muscular dystrophies. A summary of the Workshop is available on the NIAMS web at: www.nih.gov/niams/reports/fshdsummary.htm.

Research registry: In September of 2000, the NIAMS and the NINDS funded a research registry for FSHD and myotonic dystrophy. The long-term goal of the registry is to facilitate research in FSHD and myotonic dystrophy by serving as a liaison between families affected by these diseases who are eager to participate in specific research projects, and investigators interested in studying these disorders. The registry, based at the University of Rochester, will recruit and classify patients, and store medical and family history data for individuals with clinically diagnosed FSHD and myotonic dystrophy. Scientists will be provided with statistical analyses of the registry data, as well as access to registry members who have agreed to assist with particular research studies. The national registry will serve as a resource for scientists seeking a cure for these diseases, in addition to enhancing research to understand what changes occur in muscular dystrophy.

Research solicitations: In November of 2000, the NIAMS and the NINDS jointly issued a request for applications for exploratory research on FSHD. This announcement is designed to encourage research proposals using creative, novel, potentially high risk/high payoff approaches that could produce innovative advances in this field. Successful projects may include feasibility studies, clinical protocol planning, and efforts to incorporate new disciplines and technologies into the study of FSHD. In developing this solicitation, the NIH built on the insights we gained from the scientific conference cited above. Based on that conference, we have focused this new request for research proposals on issues related to improving our understanding of the origins of this disease and how to characterize its molecular basis. Among other areas, such projects could include studies looking at changes in muscle as FSHD develops; exploring the role of inflammation in this disease; and creating new models of FSHD that could facilitate the eventual development of effective therapies.

In January of 2001, NIAMS and NINDS partnered again to issue a program announcement with funds set aside to support research on understanding and developing therapies for the muscular dystrophies, including FSHD. This solicitation is described in the following discussion of Duchenne muscular dystrophy discussion.

Duchenne and Becker muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy, affecting approximately 1 in 3,000 male births. About one third of cases reflect new mutations and the rest are familial. Because inheritance is X-linked recessive, DMD affects primarily boys, though girls and women who carry one defective gene may show some mild symptoms.

DMD is a particularly devastating and lethal form of muscular dystrophy. When the body's attempts to regenerate muscle cannot keep up with the destructive process, muscle wasting and progressive weakness result. DMD usually becomes evident when children begin to walk. Boys typically require a wheelchair by age 10 to 12, and usually die in late teens or early 20's. Becker muscular dystrophy (BMD) is a less severe but closely related disease. DMD results from an absence of the protein dystrophin, and BMD reflects a partly functional version of the same protein.

Research conference: To explore what NIH can do to develop effective therapies for DMD and BMD, the NINDS, the NIAMS, and the NIH Office of Rare Diseases (ORD), working together with the Parent Project for Muscular Dystrophy held a "Workshop on Therapeutic Approaches for Duchenne Muscular Dystrophy" on May 15^th and 16^th, 2000, on the NIH campus in Bethesda, Maryland. An international group of experts participated in this meeting along with representatives from U.S. and European muscular dystrophy associations and NIH staff. On May 17^th, following the Workshop, the scientific organizers, topic leaders, and NIH program directors met to summarize the discussion and formulate future research priorities. A summary of the workshop is posted on the NINDS websites at: www.ninds.nih.gov/news_and_events/dmdmtngsummary.htm.

Understanding the disease: More than 15 years ago, researchers supported by the NIH and the Muscular Dystrophy Association identified the gene for dystrophin that, when defective, causes DMD and BMD. The identification of the dystrophin gene stimulated research that provided new insights and directions for research on the biology of muscle and the mechanisms of disease, as evident in thousands of high quality scientific publications and several promising leads for developing new therapies.

One challenge the dystrophin gene presents is its enormous size. The gene is the largest gene yet identified in humans. Most vectors (usually modified viruses) available for gene replacement cannot incorporate a gene of this magnitude. The size probably also contributes to the high rate of new mutations in the gene and to the large number of different mutations that can occur within the gene. Definitive therapy may require precise knowledge of the particular gene defect in each patient.

The dystrophin protein was unknown before the discovery of its link to DMD. Subsequent studies have revealed that dystrophin is part of a complex structure involving several other protein components. The "dystrophin-glycoprotein complex" helps anchor the contents of muscle cells through the cells' outer enclosing membrane to the material in which muscle cells are embedded. Defects in this assembly lead to structural problems that can disrupt the integrity of the outer membrane of muscle cells, resulting eventually in degeneration. One of the most remarkable spin-offs from the elucidation of the complex has been clarification of the interrelationships among DMD and other forms of muscular dystrophy. Several other forms of muscular dystrophy, whose relationships to DMD were obscure, result from mutations in other protein components of the same dystrophin-glycoprotein complex. These include several forms of limb girdle muscular dystrophy, named for the characteristic pattern of muscle weakness. Research to more fully understand the normal and abnormal functions of the dystrophin complex, and of other proteins closely related to dystrophin, is ongoing, and evidence is accumulating that these proteins play important roles in the brain as well as in muscles.

Therapeutic approaches: Several new approaches have emerged for developing therapies to stop or reverse muscle degeneration in Duchenne muscular dystrophy. All of these strategies rely upon increased understanding of the underlying biology of the disease. However, one point made at the May workshop is the extent to which novel therapeutic strategies for DMD arise from research that is not focused on muscular dystrophy, muscle biology, or even therapeutics in general.

Logically, the simplest approach to treating DMD might seem to be to supply a good copy of the defective gene. An important advantage in studying DMD is the availability of the mdx mouse which is a useful model of the human disease. Results in mice with the same gene defect as DMD show that modified virus "vectors," such as the adeno-assocated virus, can carry the therapeutic genes into muscle cells and partially reverse the disease. Recent experiments have also shown that a genetically engineered "mini-dystrophin," while much smaller than the natural form, seems able to carry out its essential functions. However, considerable advances are needed to make gene replacement workable for children with MD. The technology of gene replacement is just beginning to yield clinical success in some of the simplest diseases to treat. Treating DMD presents special problems not only because of the large size of the gene, but also due to the need to deliver the gene reliably and safely to muscle cells throughout the body. Improving the delivery of genes to muscle, optimizing the control elements that regulate the activity of therapeutic genes, and minimizing immunological and other potential safety problems are on-going areas of research. The first preliminary gene replacement trials for any form of muscular dystrophy have been designed by MDA for a form of limb girdle muscular dystrophy caused by a defect in a component of the dystrophin-glycoprotein complex.

Several other approaches to counteracting the gene defect, besides gene transfer by viral vectors, also show promise for DMD. The use of "naked DNA" is one approach under investigation for several diseases that may be applicable to DMD. Another approach uses chimeraplasts. These specifically designed synthetic molecules are hybrids of DNA and RNA that can guide the muscle cells' own repair machinery to correct some types of defect in the dystrophin gene. "Antisense" nucleotides are another type of synthetic molecule that has therapeutic potential. These molecules, which are designed to bind specifically to certain parts of genetic material, alter how the cells' internal machinery reads a gene to make protein, thus compensating for certain types of defects in dystrophin. Another strategy uses aminoglycoside antibiotics. Some children with DMD (perhaps 15%) carry a mutation in the dystrophin gene that creates an erroneous DNA code signal to stop making the protein. Dr. Sweeney, who will also testify today, did experiments in mice with the same types of errors in dystrophin and found that antibiotics can cause the protein synthesizing machinery to ignore stop signals and allow muscle cells to make enough dystrophin. Gentamicin, an antibiotic of this type, is now being tested in clinical trials for DMD in children.

Finally, drug therapy for DMD has also been a focus of research efforts. One approach has used high-throughput screening (HTS) to try to find drugs that increase the muscle production of another protein, utrophin, that can help compensate for the loss of dystrophin. High throughput screening employs robotics and miniaturized assays (tests) to screen thousands of chemical compounds quickly to find leads for further drug development. Other pharmacological research areas of continued interest for DMD relate to the use of corticosteroids in the disease and to strategies informed by increased understanding of immunology and its relation to DMD.

Solicitations: As noted above, in January 2001, NINDS and NIAMS issued a PA-S (program announcement with set-aside) entitled "Therapeutic and pathogenic approaches for the muscular dystrophies" to encourage research in areas highlighted as priorities at the DMD and FSHD workshops and in areas important for other forms of muscular dystrophy. The PA-S, unlike a regular PA, sets aside funds ($5 million) for the purpose of this research. Unlike an RFA (request for applications), this mechanism does not restrict researchers to a single deadline for proposals. Unsuccessful applicants are encouraged to reapply after improving their proposals based on the suggestions of scientists on peer review panels.

Several other actions of NINDS, NIAMS and other components of NIH address priorities for muscular dystrophy research that also have implications for other disorders. These include extensive efforts, through workshops, solicitations, and other actions, to promote new technological approaches, such as gene replacement, and to encourage exploratory grants from researchers not currently working in the field. Planned workshops will also focus on issues such as review of steroids for treatment of DMD and clinical trial design for testing of these drugs and issues in screening of newborns for eventual identification of DMD when a treatment is available. NINDS has also placed an increased emphasis on expediting clinical trials for neurological disorders. In addition to grant mechanisms for pilot trials and planning of large trials, the Institute is enhancing its ability to work with researchers to design and conduct clinical trials. NIAMS is also supporting planning grants for clinical trials, including one on myotonic dystrophy.

In recent years, NIAMS and NINDS have also worked together to strengthen NIH Intramural research in muscle biology and disease. The Institutes have recruited outstanding scientists to lead research programs in this area. One consequence, for example, is that the resources of the NIH Intramural program have been used to expedite clinical trials of gentamicin therapy of DMD and to discuss the implications of findings so far with this strategy.

Concluding remarks:

The muscular dystrophies impose enormous burdens on people with these disorders and on their families. We at NIH recognize the need to target increased efforts against the muscular dystrophies. We are doing so through the workshops, then following up with targeted solicitations for applications, including set-aside funds designed to recruit new investigators to the field, and through other efforts in both extramural and intramural programs that I have cited above. The promising opportunities for developing therapies build upon what we have learned about these disorders, and we must continue to learn more even as we move toward testing the best candidate therapies. It is also worth noting that the therapeutic strategies we are now investigating arose from research not targeted to these diseases, so we must maintain a broad front of progress in neuroscience, muscle disorders, and biology generally.

Finally, we at the NIH want to recognize the contributions of the foundations represented here today-the Muscular Dystrophy Association, which for years with the tireless efforts of Jerry Lewis has fostered research in muscular dystrophy and other neuromuscular diseases, and the Parent Project, which has brought a renewed sense of urgency to the field. The NINDS stands ready and able to work in partnership with these organizations and others in the U.S. and abroad to take the lead in a new strategy that will build on all we have learned in the past 15 years and bring effective treatment for muscular dystrophy patients. We appreciate your efforts in increasing funding for NIH overall and the NINDS in particular, and we dedicate ourselves to the task of putting this money to the best possible use in helping patients with these diseases.

Mr. Chairman, I appreciate the opportunity to discuss these disorders, which have long been a major concern of mine, and I am pleased to respond to any questions you may have.