Why the Wellstone MDCRCs Were Established

How the Wellstone MDCRCs Function Within the NIH Framework

Description of Disease or Condition

• Duchenne and Becker muscular dystrophies: Duchenne muscular dystrophy is the most common childhood form of muscular dystrophy. It is an X-linked recessive disease, primarily affecting males who inherit a genetic mutation from their mothers. Boys with Duchenne muscular dystrophy lack the protein dystrophin, which is essential for keeping muscle cells intact. Duchenne muscular dystrophy usually becomes evident when a child begins walking. Patients typically require a wheelchair by age 10 to 12 and die in their late teens or early twenties. Becker muscular dystrophy, a less severe disease, occurs when a partially functional form of dystrophin is produced.
• Myotonic dystrophy: Myotonic dystrophy is the most common adult form of muscular dystrophy, although it can strike at any age. It is marked by myotonia (an inability to relax muscles after contraction) and muscle wasting and weakness. Myotonic dystrophy varies in its severity and manifestations. It can affect other body systems in addition to skeletal muscles, including the heart, endocrine organs, eyes, and gastrointestinal tract.
• Facioscapulohumeral muscular dystrophy: Facioscapulohumeral muscular dystrophy initially affects muscles of the face (facio), shoulders (scapulo), and upper arms (humeral). Symptoms usually develop in the teenage years, and some affected individuals become severely disabled.
• Limb-girdle muscular dystrophies: All limb-girdle muscular dystrophies show a similar distribution of muscle weakness, affecting both upper arms and legs. Many forms of limb-girdle muscular dystrophy have been identified; some affect children, whereas others manifest in adulthood.
• Miyoshi myopathy: Miyoshi myopathy, one of the distal muscular dystrophies, causes initial weakness in the calf muscles. It is caused by defects in the same gene that is responsible for one form of limb-girdle muscular dystrophy, suggesting that research progress against one form of muscular dystrophy may lead to a better understanding of other forms as well.

Burden of Illness

Scope of NIH Activities: Research and Programmatic

• The University of Pittsburgh center focuses on developing gene therapy techniques as well as research on muscle stem cells as potential therapies for Duchenne muscular dystrophy. The center is also preparing to conduct a clinical trial of gene therapy for limb-girdle muscular dystrophy.
• The University of Rochester center focuses on myotonic dystrophy and facioscapulohumeral muscular dystrophy. Researchers are examining cellular and molecular factors that contribute to these diseases and are conducting a clinical trial of the drug IPlex (mecasermin) for patients with myotonic dystrophy.
• The University of Washington center focuses on gene therapy techniques and has begun several new collaborative projects focused on the mechanisms underlying facioscapulohumeral muscular dystrophy
• Researchers at the Children's National Medical Center are analyzing genetic and cellular factors that contribute to the progression of Duchenne muscular dystrophy and the response of patients to treatment.
• The University of Iowa center focuses on gene and stem cell therapeutic strategies for Duchenne, limb-girdle, and other muscular dystrophies. It provides diagnostic services for physicians around the country and banks biopsy samples that can be used for research.
• The University of Pennsylvania/Johns Hopkins University center focuses on strategies to promote muscle growth or inhibit muscle protein degradation, approaches that could be applicable to a range of muscular dystrophies and other muscle disorders. It also provides state-of-the-art animal model physiological testing services as a resource for other researchers.

NIH Funding for FY 2006 and FY 2007

Programmatic Accomplishments

• A collaborative effort between investigators at the Wellstone MDCRC at Children's National Medical Center and researchers in Japan to evaluate a gene modification technique (i.e., exon skipping) in a dystrophic dog model
• Collaboration between the Iowa Wellstone MDCRC and Ohio State University to develop more effective diagnostic techniques for limb-girdle muscular dystrophy and Miyoshi myopathy
• A partnership between University of Pittsburgh and University of Pennsylvania investigators to study myostatin inhibition using the dog colony supported by the Pittsburgh Center

Research Accomplishments

• In the past 2 years, investigators at the University of Rochester MDCRC have begun a clinical trial to test the drug IPlex in patients with myotonic dystrophy. The dose escalation phase of this safety and feasibility trial suggests that the drug is well tolerated. The next phase of the trial will test an optimal dose in patients with myotonic dystrophy. Because IPlex improves muscle regeneration, it may be useful in many types of muscular dystrophy.
• Two other clinical trials, including one to test a gene therapy for limb-girdle muscular dystrophy, are preparing to begin recruiting patients.
• Wellstone MDCRC investigators have made numerous other advances with respect to gene therapies for other muscular dystrophies. Many strategies that 2 years ago were being tested in mice are now being evaluated in dogs. Wellstone MDCRC researchers are refining their technologies and are identifying how genes should be administered. They also are discovering interactions between gene therapy vectors and human immune responses and have developed an immunosuppression protocol that shows promise in dogs. ¹⁶
• Researchers at the University of Pennsylvania/Johns Hopkins University Wellstone MDCRC have tested a class of compounds known as protease inhibitors (i.e., Bowman-Birk inhibitors) that show promise in animal models of Duchenne muscular dystrophy and are planning to begin a clinical trial.
• The Wellstone MDCRCs are also contributing basic research findings to the understanding of muscular dystrophy. For example, during a search for stem cell traits that predict effective muscle regeneration, University of Pittsburgh researchers determined that cell sex (i.e., whether the cells originated in a male or a female donor) has a profound influence on whether muscle stem cells can produce muscle fibers in a mouse model of Duchenne muscular dystrophy¹⁷. The results could influence future research on the use of cell transplants for treating muscular dystrophy and affect the overall field of stem cell biology and regenerative medicine by prompting other investigators to consider and report the sex of the cells used in their research.
• In other basic research, investigators at the University of Rochester conducted a comprehensive genome-wide scan of biopsies from patients with early-stage facioscapulohumeral muscular dystrophy. The scan results are dispelling a widely held belief that a deletion on chromosome 4 triggers the development of facioscapulohumeral muscular dystrophy by disrupting expression of neighboring genes¹⁸. Results from this study have connected vascular abnormalities commonly observed in the retinas of patients with facioscapulohumeral muscular dystrophy who have the skeletal muscle weakness and wasting characteristics of the disease and may eventually lead to new treatments of this disease.

Recommendations for Improving the Effectiveness, Efficiency, and Outcomes of the Wellstone MDCRCs

• Whereas the Wellstone MDCRCs established in 2003 and 2005 have three research projects, an administrative core, and a scientific research core, institutions applying for the program in FY 2008 are required to have at least one research project and specific core activities.
• Because the number of basic findings that are ready for translation has increased dramatically since the last competition, NIH removed the basic research requirement to allow the Wellstone MDCRCs to focus more of their efforts on translational research.
• The need for a clinical or patient-oriented project remains unchanged in the new solicitation, but because the required number of projects has been reduced from three to one, center applicants are free to propose larger, more expensive clinical research activities.
• Whereas the existing centers could apply for a training supplement to support the career development of a postdoctoral and nontenure track investigator, the training aspect of the next round of Wellstone MDCRCs will be formalized by Research Training and Education Cores that will support a predoctoral student and a postdoctoral fellow at each site. This addition was made in response to suggestions from the Steering Committee, combined with an analysis of existing training opportunities in the field of muscular dystrophy research.
• To better promote coordination of information and resources among the Wellstone Centers and throughout the muscular dystrophy research community, each applicant institution is required to provide letters documenting how one of its proposed core resources will fill a high-priority need in the muscular dystrophy research community.

Evaluation Plans

Future Directions