Meeting Reports 2002

NIH Muscular Dystrophy Research Task Force Summary

May 15-16, 2002 (historical)

At this first meeting of the NIH Muscular Dystrophy Research Task Force, the participants agreed that the immediate goal is to add new capabilities to the national effort to understand and treat muscular dystrophies. New support should be used to enhance research efforts and not duplicate existing programs or projects. Participants identified several key issues to be addressed in furthering research and care for muscular dystrophy patients. Efforts must be made to attract talented researchers from very diverse scientific fields and medical specialties, by ensuring that there are career paths and an identifiable muscular disease (myology) expertise and community. There must also be programs to support training that increases exchange of techniques, information, and ideas. The following items were also encouraged: support for research centers that promote side-by-side basic, translational, and clinical research; resources that can be used by the national research community; and training and advice about muscle diseases for researchers and physicians who provide initial diagnosis and treatment.

Researcher Development and Training Issues

Further research requires new investigators who have varied skills; the challenge identified was the ability to attract researchers from the diverse backgrounds to enhance discoveries in muscular dystrophy. As such, muscular dystrophy research and clinical care require expertise in muscle biology, genetics, imaging, muscle plasticity, exercise science, nutrition, molecular biology, neuroscience, rehabilitation medicine, epidemiology, clinical trials, bioengineering, electrophysiology, psychology, behavioral sciences, and other branches of clinical medicine.

Since the muscular dystrophies involve diverse medical disciplines, including neurology, rheumatology, cardiology, orthopedics, pediatrics, medical genetics, physiatry, and rehabilitation practitioners, the challenge is to find ways to facilitate interactions, and to build upon the strengths of divergent disciplines. It may be best to start by providing additional support where there is a record of interdisciplinary research and cooperation; muscular dystrophy research centers with training components might be a viable approach. Another target would be to develop new, focused training programs that would link clinical and basic science researchers.

In order to address the issue of subspecialty of clinical training, creating a clear career path in the area of myology would be novel. The time may be ripe for such subspecialty development based on the establishment of groups such as the United Council on Neurologic Subspecialties, which are fostering special expertise for clinical neuroscientists.

Many physician-researchers develop their research interest based on early identification with clinical fellows, who become role models. It is necessary to expose medical students to the area of muscular dystrophy at an early stage of their training. Current researchers need the stimulus and support to be aggressive in recruiting people and doing it at the optimum time. Perhaps voluntary groups could help attract new clinical investigators. It would be useful to have muscular dystrophy, or myology, clinical fellowships.

Participants mentioned several possible models of support for research training, including the National Institute of Child Health and Human Development (NICHD) Pediatric Scientist Training program and National Center for Medical Rehabilitation Research (NCMRR) Rehabilitation Medicine Training Centers. The Pediatric Scientist Training program is a nationwide program, which currently supports thirty postdoctoral fellows. Originally initiated by chairs of pediatric departments, it is funded partially by Federal and private sources. Applications for candidates are prepared by candidate and mentor, and reviewed by the training program director and an advisory committee. Stipends for fellows are at a higher level than regular training programs. Trainees can then apply for other research career development awards and regular research grants. Adapting existing organizational models could help meet the current muscular dystrophy research training needs.

Promoting a Community of Researchers

It is necessary to further the self-identification of a community of researchers involved with muscular dystrophy. This effort must have the focus on muscle in order to keep the involvement of muscle biologists and be designed to bring together groups that currently do not attend meetings in common. Wide representation of interested communities would promote discussions of common interests, including presentations on translating results from one research area to another.

One approach is to have an annual meeting, which would be a smaller version of the current international neuromuscular diseases meeting in Vancouver. Topics would cover the general area of myology, including, as appropriate, additional subjects such as inflammation and disuse atrophy, as well as a number of molecular and cellular topics pertinent to muscle diseases. More intensive workshops could focus on subjects such as a common lexicon (dictionary), diagnostic criteria and treatment strategies. In these workshops, small groups could develop proposals to be presented at national meetings. Meetings could be planned by a small group concentrating on goals, scope and advantages of themes. The group could then develop the content necessary to apply for conference grants from the NIH and other funding agencies.

Resources to Further Muscular Dystrophy Research

The Task Force mentioned additional resource needs.

  1. Mechanisms to encourage cooperative research, innovative/high risk research, and translational research. Efforts to further research in muscular dystrophy must find ways to identify innovative approaches and then identify the people who are best able to do the research. Funding components need to actively solicit applications. This occurred in establishing research cooperation to search for the gene for dystrophin.
  2. Repositories of tissue, DNA, cell lines, and other shared research resources and materials must be developed.
  3. Forums for the exchange of scientific information and collaboration. It would be useful to have a data exchange platform, such as a website, for information about stem cell research. A similar platform could be used to identify animal models and their locations.
  4. Animal models and resources are critical. It is necessary to continue partnerships such as those with Jackson Labs. It might be useful to have a committee identifying high priority models to generate. Some diseases, such as facioscapulohumeral muscular dystrophy (FSHD), might need research cores to generate animal models.
  5. Informatics (data sharing, common protocols, core dictionaries, mechanisms for combined analyses, intellectual property issues, recruitment systems) and biostatistical design and analytical needs.
  6. Resources for genetics, pathology, reagents, biophysics, muscle imaging, proteomics, ethics and policy consultation (diversity and cultural competence, consent, privacy).

In the discussion, the successful examples of the National Cancer Institute's (NCI) childhood cancer group and the web site for Gene Tests/Gene Clinics were mentioned, as was the NCI's Mouse Models of Human Cancer Consortium. These constitute good models for the types of collaborative groups and resource programs that could help meet the muscular dystrophy program goals.

Centers

Research centers can play an important role in promoting the exchange of ideas and information between basic and clinical investigators. The centers should have a broad approach, including plans to move new knowledge to a clinical setting. Centers should build on existing research programs, but can be at multiple sites. They may have differing areas of focus, including research resource cores and both basic and clinical research. Centers should actively develop ways to allow and encourage collaborative research with other investigators. It is important that each center for muscular dystrophy research include components in training, clinical/translational research, and basic science. They should be structured to promote clinical trials, interactions with industry, and provide training and advice about muscle diseases for researchers and physicians who provide initial diagnosis and treatment.

Clinical Issues

In order to promote clinical studies in the muscular dystrophies, it is necessary to deal with challenges in diagnosing patients. Primary care physicians and patients would benefit from consultive help and laboratory backup. For example, few individual clinics have the capacity to definitively diagnose a patient with limb-girdle muscular dystrophy (LGMD). The phenotype is not sufficient, as protein deficiencies may cause wide discrepancies. At the moment, there is little training in molecular-based diagnosis. It may be valuable to use algorithms that proceed by successive steps, minimizing the number of tests ordered. The choice reflects a thought process about what information is needed to differentiate between a successively smaller number of possible diagnoses.

There are limitations even after extensive characterization by molecular diagnosis, since even the single term Duchenne muscular dystrophy (DMD) is a collection of many different mutations. It can make it very difficult to get sufficient numbers of patients for a clinical trial. This limitation can be overcome by studying shared pathophysiological mechanisms. It may be necessary to explore alternative clinical study design.

Priorities

  1. Identifying innovative approaches that will provide the best return on investment.
  2. Improving institutional training environment and infrastructure, with a focus on myology.
  3. Promoting a translational research infrastructure for clinical trials, etc.
  4. Programs to stimulate innovative research using animal models, etc.
  5. Development of new therapeutics.
  6. Improved diagnostic resources for research and clinical practice, including algorithms combining phenotypic and genotypic analysis.
  7. Increased research on mechanisms of muscle disease and understanding muscle and degeneration.
  8. Partnerships with industry to promote pharmacologic and gene-based therapies.
  9. Epidemiologic resources (registry/surveillance).
  10. Education of primary care providers.
  11. Basic research on mechanisms for the muscular dystrophies.