Meeting Reports 2003

NIH Muscular Dystrophy Research Task Force Summary

January 21-22, 2003 (historical)

At this second meeting of the NIH Muscular Dystrophy Research Task Force, members focused on organizing research efforts in ways that would improve treatment for all forms of muscular dystrophy. Collectively, the muscular dystrophies have significant health, economic, and social impacts. Aspects of several forms of muscular dystrophy share symptoms with other disorders of muscle, including disuse and age-related atrophy, which affect even larger population groups. Research that is coordinated to produce standards of care would greatly improve the understanding and treatment of the muscular dystrophies. Developing consortia to improve information about the muscular dystrophies and other muscle disorders, and disease outcome measures will provide a basis for multi-center studies of new treatments. One aim of this approach would be to provide patients with muscular dystrophy access to state-of-the-art therapies. This can be coupled with increased collaborations with industry and other research groups to promote the development of pharmaceutical and other therapies.

Disease Manifestations

The varied clinical manifestations of muscular dystrophy provide many opportunities for treatment. It is important to consider how patients perceive limitations imposed by their conditions. A quality of life survey of patients with muscular dystrophy indicated that major limitations were due to weakness, difficulty getting exercise, and fatigue. People with other conditions that result in severe muscle deconditioning have the same challenges.

Severe muscle wasting and degeneration are common to muscular dystrophies, and the pattern of muscle wasting provides a historical basis for disease classification. Most characterizations are currently based on external observation and measurement, and it is challenging to differentiate between lean and fibrotic (scar) tissue, as well as lean and fat tissue. It is not clear which aspects of decreasing muscle strength are due to disease progression and which to atrophy secondary to a sedentary lifestyle. Constrained mobility almost certainly causes some disease complication. Contractures are partially due to stationary conditions; knee-contractures usually develop soon after patients are limited to movement in wheelchairs. Transition by a patient to a wheelchair also contributes to increased spinal curvature, either lateral (scoliosis) or backward (kyphosis). Other major manifestations that, to varying degrees, occur in different forms of muscular dystrophy include respiratory problems, cardiomyopathy, and behavioral and cognitive impairments.

Treatment Goals

The focus for treatment should be disease management, aimed at restoring normal quality of life and promoting physical activity. Progressive muscle weakness contributes to major complications of muscular dystrophy, including constrained mobility, contractures, impaired breathing, and increased cardiac abnormalities. It is important to define the role of exercise in alleviating or exacerbating symptoms. The highest priorities for treatment should be on reversing skeletal muscle wasting and weakness, preventing respiratory failure, and preventing cardiomyopathy. Additional priorities are to prevent contractures, and limit multi-organ involvement and cognitive impairment. It is important to address psychosocial issues that accompany muscular dystrophy, and lessen the impact of the diseases on other family members, carriers, and care givers.

Targeting Specific Systems

Since there are patterns of damage in muscular dystrophy, there may be advantages to targeting specific muscle groups, such as those responsible for respiration, postural control, ambulation, fine motor control, and cardiovascular function. Treatment may be aimed at decreasing muscle degeneration, increasing muscle mass, increasing the number of regenerative cells (myocytes), increasing strength, or decreasing contractures.

Cardiac manifestations include ventricular and atrial dysfunction, and problems with conduction. Standard pharmaceutical agents for other heart disorders need study in the muscular dystrophies. There is secondary involvement of the vasculature, suggesting novel targets for treatment.

Challenges to Effective Treatment

Incomplete knowledge limits current medical management of muscular dystrophy patients. In many cases, molecular tests provide a diagnosis, but do not fully characterize the nature of the genetic defect. Treatment approaches vary considerably, influenced by geographic location and initial health care provider. There is no uniformity or consensus on treatment and management of patients.

Commercial testing is available for several forms of muscular dystrophy, including Duchenne and Becker, myotonic, facioscapulohumeral, and oculopharyngeal. It is necessary to increase access and reimbursement for these tests, and expand commercial laboratory-based diagnosis for other muscular dystrophies. Currently, clinicians depend on research laboratory procedures, which are not approved for medical purposes. Further, such laboratories are seldom reimbursed by third-party payers. There is a similar challenge for diagnosing patients with hypertrophic cardiomyopathies.

In order to improve treatment, it will be necessary to better correlate information about disease treatment and progression in current patients. There is little direct medical justification for collecting detailed information on disease progression if there is no current treatment. Yet, it is difficult to do an approved trial if there are no natural history data for the particular muscular dystrophy. Drug trials will require sensitive and reliable outcome measures of deterioration of muscle strength and quality. The information and treatment needs could be addressed by muscular dystrophy clinical study consortia. There are successful models for this approach, including the Children’s Oncology Group, funded in part by National Cancer Institute and insurance companies. It is aimed at looking at molecular signatures for childhood cancers. In the case of muscular dystrophy, all patients would have the opportunity to have data entered into a uniform system. This requires commitment by patients and investigators.

Current and Emerging Therapies

Currently, there are several active and emerging therapeutic approaches for the muscular dystrophies. The most effective clinical approach may be combined treatment. Some approaches offer exciting possibilities, but it is not clear when they are likely to be practical and available for widespread use. This is especially true for therapies based on genetic approaches. It is difficult to estimate the time frame for development of delivery systems that will enable effective targeting of skeletal muscles. While numerous gene delivery systems are being tested, it remains unclear whether the ideal vector system has been developed. Basic issues such as vector size and capacity, potential toxicity, and immune profile need further clarification. The value of local vs. systemic gene delivery is an issue that needs greater study. Finally, there is a great need for the development of methods to target muscles throughout the body with gene or cell-based delivery vehicles.

Cell-based therapy can take advantage of the fact that skeletal muscle is formed by the fusing of individual cells, but there remain critical challenges. The uptake of cells is very low and appears to require a signal of muscle injury, perhaps including the vasculature. Data suggest that muscle that is damaged is more efficient than healthy muscle in incorporating circulating stem cells. Effectiveness, though, depends on the condition of the muscle. Tissue that is less damaged can be better restored to near normal function, suggesting that treatment should begin as soon as possible. Screening of newborns will facilitate early treatment. More knowledge is needed about the basic biology of precursor cells for muscle development and repair (myogenic), and methods to encourage their ability to find sites of muscle damage and lead to repair.

Other approaches include the use of small molecules, and genetic modification of secondary targets, such as myostatin, insulin-like growth factor-1 (IGF-1), integrins, and nitric oxide synthase (NOS). These might not have the delivery and immune problems of dystrophin or other proteins related directly to disease. Such approaches require a better understanding of muscular dystrophy pathogenesis, such as the pattern of affected muscles, which is different in the different diseases. An important question in myotonic dystrophy is how a toxic ribonucleic acid (RNA) causes muscle dysfunction, and whether conventional pharmaceutical approaches can be developed to help muscle cells degrade this toxic material. Another question is the total role of dystrophin, which appears to have structural and signaling aspects. Increased expression of utrophin, a dystrophin-like protein, appears to improve muscle health in a mouse model, but a similar role in other animals has not been shown.

The use of small molecules includes corticosteroids and related molecules. Though current treatment includes prednisone and deflazacort (outside the United States), we do not yet know the mechanism of action, nor the effect on the muscle within the heart wall. There is little information about how the substances are currently used, so there is need for additional studies to establish standards of care with steroids. Gentamicin, which is also under study, may be of use for a small number of DMD patients. There are traditional interventions, including orthopaedic intervention and use of orthotic devices, that would benefit from having natural history data.

Promoting Development of New Therapies

To develop therapies, the muscular dystrophy research community needs a scientific agenda based on current research personnel, institutional, and organizational resources. It is important to look for responders to treatments. The number of initial responders may not represent a large group, but their response provides a beginning in improvement for the disease area. Treatment is usually improved by small incremental increases. An example is improved treatment for childhood leukemia which was based on the search for modest modifiers.

Several resources exist within the Federal government to promote new treatments for limited populations. The NIH Office of Rare Diseases (ORD) sponsors workshops and conferences. ORD will identify interventions that are not being studied and facilitate the development of a screening process, similar to what was done in cancer.

Within the Food and Drug Administration (FDA), the Office of Orphan Products Development handles issues relevant to muscular dystrophy treatment. This office oversees an incentive package that can be made available to industry to encourage drug development. The grants are limited by law to clinical trials, specifically phases II and III, for a maximum of three years. They are closely managed. Comparison studies to establish standards of care might be eligible for funding by FDA’s grant program.

It is important to bring in industry, since they may be potential funding partners. Representatives from companies should be involved from the early planning stages when considering the development of new therapies for the muscular dystrophies, since studies need to generate data compatible with FDA and industry standards. Costs to a company of developing a product are usually higher the earlier it becomes involved. Sometimes a company might provide data monitoring for right-of-first-refusal. One needs to negotiate a separate agreement for each drug. There are many tools, and one needs to determine which are the best fits with a particular product. For example, NIH could fund a comparison of deflazacort against some other generic corticosteroid, or a study to determine optimum treatment time and dosage for prednisone. There may be different levels of involvement with the big vs. smaller pharmaceutical companies.

A drug can never become a product without industry involvement. The process of development for a product, from first concept to market, is costly. One needs to find ways to increase the marginal value of new drug products that may have limited markets, especially for small companies. Companies with limited product development capacities may be most receptive to encouragement by public funding.

Though it can be profitable to market to small populations, pharmaceutical companies need a significant return on their investments. Thus, marketing to a limited population may mean that drugs are expensive. It is not clear what prices the public is willing to pay. There may be ways of inducing companies to do more work by creating new or additional incentives, such as extension of exclusivity for other drugs (which has worked in cases of pediatric drug testing), or protection from liability.

Patient support groups are important as well. Reimbursement is always a major issue, so it is essential to have discussions and collaborations with insurance companies and sponsors of protocols, as well as representatives of patient groups.

Outcome Measures

Skeletal muscle-specific outcome measures and validated surrogate markers are necessary for improved studies on treatments for muscular dystrophy. Outcomes from muscle diseases may be complex and subtle when compared to mortality. There are limitations to accepted and readily applied measures. Clinical consortia aimed at trials for muscular dystrophy will need to define eligibility criteria, with accurate molecular diagnosis, and provide for standardization of data collection.

Measures to document changes in strength are crucial, and can be measured with manual muscle testing (MMT) or with quantitative methods using dynamometry. It is necessary to connect such measures to a disease-specific functional grade, since the same percent increase of strength will make a difference in function depending on the state of the patient.

Movement assessments are also important measures. Kinematic analysis of upper extremities, combined with timed motor performance, accurately predicts when DMD patients will make a transition to wheelchair dependency. Other useful measures of physical activity include step activity monitor, and real world mobility. Studies of muscular dystrophy can use existing outcomes measures for pulmonary, cardiac, and cognitive complications, since such complications occur in more common diseases.

Determining soft tissue mass and quality is crucial. It is important to be able to monitor such changes during the course of disease and treatment. Dual energy X-ray absorptiometry (DEXA) is a valid measure of mass, but provides no axial information, nor does it completely distinguish muscle, fat, and fibrotic (scar) tissue. DEXA measurements in DMD patients show that there are greater muscle deficits in legs than arms. Magnetic resonance imaging (MRI) is also promising. As it is currently used, it does not clearly distinguish between muscle and fibrosis. A modified technique used on mice shows the degree of integrity of the sarcolemma, the membrane surrounding muscle fibers, which is disrupted in some muscular dystrophies. Functional MRI, as used in cancer and brain disorder diagnoses, can be refined to give information about metabolic activity within muscles.

It is also necessary to develop disease-specific measures for quality of life, including some personal goals of patients. As well, the field needs improved diagnostic tests to provide high- speed molecular diagnosis, so that clinical centers can provide diagnosis efficiently and effectively. There needs to be an immediate, systematic approach to longitudinal assessment, with serial data collection, so that we can judge current and future treatments. This should aim to include all muscular dystrophy patients, independent of whether they are involved in a treatment protocol.

Though there is little effective treatment at present, it might be advisable to plan for screening of newborn children, starting with state health agencies for demonstration projects. There is need for molecular approaches for diagnosing all forms of muscular dystrophy. Further, it is important to have discussions of ethical and social issues with respect to individuals with muscular dystrophies, members of their families, and care givers.

Future Opportunities

Opportunities to improve treatment exist in the areas of vector development for gene-based treatments, cell-based treatments, and substances leading to muscle repair and hypertrophy. Involving companies may require more effort by the research and patient communities and more financial incentives. It is important to consult with companies to avoid duplication of effort, such as identifying whether compounds have already been tested. Investigators in contact with representatives of the pharmaceutical industry may wish to find ways to increase interactions with researchers and patient populations.

Several priorities identified by the Task Force include the need for the muscular dystrophy community to develop plans for clinical trials. This could be initiated by compiling a table of what we know about care and outcomes today, including the beginning of a systematic approach to longitudinal assessment. A model might be based on the current effort to promote research on childhood immune diseases. One immediate focus might be late-stage medical management, where there can be a significant impact on quality of life. Another issue is to look at disease effects on smooth muscle, such as swallowing, digestion, and other gastrointestinal issues. These complications interfere with speech and affect self-esteem. A goal would be to establish best practices and standards of care. Establishing a muscular dystrophy treatment and management consortium might be best initiated through funding of clinical studies that require widespread participation. Steps should be taken to promote coordination between existing cooperative groups. The development of novel and experimental therapeutics, such as those based on gene or cell therapies, will likely require smaller clinical trials that would progress to more widespread trials only after demonstrating initial safety, and at least minimal efficacy.