NIH Centers of Excellence
Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers
Why the Wellstone MDCRCs Were Established
The Muscular Dystrophy Community Assistance, Research and Education Amendments of 2001 (the MD-CARE Act, Pub. L. No. 107-84) specified
provisions for expanding and intensifying research on muscular dystrophy and mandated that NIH establish Centers of Excellence for
research on muscular dystrophy. Congress designated the centers as the Senator Paul D. Wellstone Muscular Dystrophy Cooperative
Research Centers (Wellstone MDCRCs) in the Omnibus Appropriations for FY 2004 (Pub. L. No. 108-199). Former Minnesota Senator
Paul D. Wellstone, who died on October 25, 2002, was a driving force behind the Muscular Dystrophy Community Assistance
Research and Education (MD-CARE) Act (see Table 4-3).
How the Wellstone MDCRCs Function Within the NIH Framework
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NINDS, and the Eunice Kennedy Shriver National
Institute of Child Health and Human Development (NICHD) fund two Wellstone MDCRCs each, using the U54 Specialized Centers Cooperative
Agreement award mechanism. A Steering Committee oversees scientific coordination of the Wellstone MDCRCs, sets goals, and makes s
trategic decisions about activities such as establishing collaborations. The committee consists of the directors
and co-directors of each center, NIH science officers, and a public member. The External Advisory Committee, which is composed
of experts in muscular dystrophy research and a patient advocate, helps inform NIH programmatic decisions regarding the Wellstone
Description of Disease or Condition
The muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive degeneration of the skeletal
muscles, which control movement. Some forms occur in infancy or childhood, whereas others may not appear until middle
age or later. Diseases addressed by the Wellstone MDCRCs include, but are not limited to, the following conditions.
- 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.
Currently, no treatment can stop or reverse the progression of any form of muscular dystrophy. Symptomatic treatments such as physical
therapy, use of appliances for support, corrective orthopedic surgery, and drugs improve the quality of life for some individuals.
However, even though some drugs, such as steroids, can slow the progression of Duchenne muscular dystrophy, there are side effects.
Several therapeutic approaches, including gene therapy, cell-based treatments, and strategies to inhibit muscle degeneration, have
shown promise in cell culture systems and animal models. Clinical trials of some therapies have begun, including the use of
drugs to reduce muscle damage, cell-based replacement therapies, functional compensation for the lack of dystrophin by increasing
the body's production of certain proteins, increasing muscle mass via inhibition of other proteins that negatively regulate muscle
growth, and strategies to bypass the mutations that cause disease.
Burden of Illness
Duchenne and Becker muscular dystrophies affect boys at a rate of 1 in 3,500 to 1 in 5,000. More than 4 million births occur
annually in the United States, and about 400 to 600 boys are born with Duchenne or Becker muscular dystrophy every year
Myotonic dystrophy affects approximately 1 in 8,000 people worldwide
whereas facioscapulohumeral muscular dystrophy affects approximately 1 in 20,000 people and affects men and women equally
The MD-CARE Act called for the Centers for Disease Control and Prevention (CDC) to collect and analyze information on the
number, incidence, correlates, and symptoms of individuals with muscular dystrophy. This surveillance system, once fully
operational, will provide additional burden of illness data.
Scope of NIH Activities: Research and Programmatic
As nationally recognized Centers of Excellence in muscular dystrophy, the Wellstone MDCRCs are expected to promote communication
and collaboration, develop and share research resources, and contribute to the training of new muscular dystrophy researchers
Each Wellstone MDCRC includes at least one basic research project and one clinical research project, with a minimum of three
individual but interrelated research projects, an administrative core, and at least one scientific resource core that
serves as a resource for the national muscular dystrophy research effort.
Collectively, the Wellstone MDCRCs are engaged in research on various forms of muscular dystrophy, including some not
listed above. Designed to accelerate progress toward effective treatments for muscular dystrophies through increased synergistic
collaboration and coordination of research activities, they promote side-by-side basic, translational, and clinical research.
Each center coordinates efforts to help bring together investigators at multiple sites.
Examples of research topics addressed at the various centers are as follows.
- 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.
The Wellstone MDCRC program reserves funds to support new collaborative projects involving center investigators and pilot projects by
non-center investigators. Center directors are also encouraged to collaborate with other muscular dystrophy researchers or representatives
from voluntary health organizations to apply for Administrative Supplements to support small workshops or conferences focused on
specific topics in muscular dystrophy research
Each of the Wellstone MDCRCs has core facilities that provide unique resources or services for the muscular dystrophy research community.
Resources include repositories of research data and biologic resources from patients with various muscular dystrophies; imaging,
diagnostic, bioinformatics, and computing capabilities; and viral vector development and production. The Wellstone MDCRC program also
aids therapeutic development by maintaining a muscular dystrophy dog colony and providing sophisticated functional testing of mouse models.
NIH Funding for FY 2006 and FY 2007
In FY 2006 and FY 2007, NIH invested a total of $9.6 million and $8.5 million, respectively, in the Wellstone MDCRC program. The
three original Wellstone MDCRCs (Rochester, Washington, and Pittsburgh) also received up to $500,000 per year from the Muscular
Dystrophy Association. This supplemental funding ended in December 2006.
Outcomes: FY 2006 and FY 2007 Progress Report
Programmatic accomplishments include awards of NIH Administrative Supplements for Senator Paul D. Wellstone Muscular Dystrophy Research
Fellowships at Wellstone MDCRCs to advance the careers of four basic and clinical scientists who study muscular dystrophy.
New collaborative projects supported by the Wellstone MDCRC in FY 2006 and 2007 include the following:
- 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
In 2006, the Wellstone MDCRC Administrative Supplements program to support workshops and research conferences funded a workshop
entitled “High Throughput Drug Screening for the Muscular Dystrophies” at the Children's National Medical Center.
Industry, academic, and government researchers, as well as patient advocates, participated. The center is planning a second workshop,
which will address the development of standard protocols for testing therapies in animal models.
The availability of Wellstone MDCRC core facilities has been publicized at national meetings, through Web sites that the centers have
established, and through the Wellstone MDCRC Web site
Sharing these research tools fosters collaborations across departments or schools at a single institution and
among investigators and health care providers at several institutions. For example, the Muscle Tissue/Cell Culture/Diagnostics Core
at the University of Iowa Wellstone MDCRC serves as both a local and a national resource for muscular dystrophy research. In addition
to maintaining a muscle tissue repository of well-characterized tissues and cells representing the spectrum of muscular dystrophy
diagnoses that are available for research, the center provides diagnostic services that are not readily available through clinical
laboratories and is facilitating the development of new diagnostic tests.
The Wellstone MDCRCs conduct basic, translational, and clinical studies related to a variety of muscular dystrophies. Each center has
at least three distinct but interrelated research projects. Examples of research accomplishments in FYs 2006 and 2007 are noted below.
- 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
- 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.
- 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
Due to NIH efforts to improve the Wellstone MDCRCs' effectiveness, efficiency, and outcomes, centers funded in FY 2008
will differ somewhat from their established counterparts
in the following ways:
- 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
- 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.
As the Wellstone MDCRC program gains momentum, NIH plans to reexamine the role and composition of the External Advisory Committee
to ensure that it continues to contribute to the growth and success of the program.
NIH reissued the RFA for the Wellstone MDCRCs in FY 2007. The competition was open to new applicants, and the three centers
that were originally established in 2003 had to compete again for funding. Major review criteria for the Wellstone MDCRCs
include the degree to which an institution demonstrates its ability to engage in substantive collaborations to address
key issues in muscular dystrophy and its potential to serve as a national infrastructure and training resource.
As noted above, the reissued RFA for Wellstone MDCRCs reflects several changes to further strengthen the program. NIAMS,
NINDS, and NICHD intend to fund up to three Wellstone MDCRCs. NHLBI will participate by supporting meritorious cardiopulmonary
research in successful applications. Grantees will join a network of existing Wellstone MDCRCs to foster the translation of new
scientific findings and technological developments into novel treatments for the muscular dystrophies
11For more information, see https://www.cdc.gov/ncbddd/duchenne/who.htm
12For more information, see https://ghr.nlm.nih.gov/condition=myotonicdystrophy
13For more information, see https://www.nlm.nih.gov/medlineplus/ency/article/000707.htm
14For more information, see https://grants.nih.gov/grants/guide/rfa-files/RFA-AR-03-001.html;
15For more information, see https://grants.nih.gov/grants/guide/notice-files/NOT-AR-05-008.html
16Wang Z, et al. Mol Ther 2007;15:1160-6, PMID: 17426713
17Deasy BM, et al. J Cell Biol 2007;177:73-86, PMID: 17420291
18Osborne RJ, et al. Neurology 2007;68:569-77, PMID: 17151338
19For more information, see https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-08-002.html