Department of Health and Human Services
National Institutes of Health
Muscular Dystrophy Coordinating Committee
November 9, 2005
Summary of Meeting
The Interagency Muscular Dystrophy Coordinating Committee (MDCC) was convened for its 4th meeting on November 9, 2005, at the Embassy Suites at Chevy Chase, Washington, DC. Dr. Stephen Katz, Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), served as Chairperson and Dr. John Porter, Program Director, National Institutes of Neurological Disorders and Stroke (NINDS) served as Executive Secretary. In accordance with Public Law 92-463, the entire meeting was held in open session.
I. Call to Order and Opening Remarks
Dr. Stephen Katz called the meeting to order at 8:30 am. He welcomed the Committee members and briefly reviewed the history and mission of the MDCC, which is to coordinate research across the National Institutes of Health (NIH) and other federal agencies for all the muscular dystrophies. He complimented the Committee on its progress to date. Dr. Katz reviewed the agenda for the meeting and noted that the Action Plan for the Muscular Dystrophies would be reviewed and discussed. The Plan will be sent to the MDCC for a vote after recommendations from the Committee have been incorporated. He also noted that translational research would be a focus of this meeting and that the committee will be hearing updates on ongoing and new activities at the NIH, Department of Defense (DOD), Parents Project Muscular Dystrophy (PPMD) and the Facioscapulohumeral Society (FSH Society). Dr. Katz welcomed public comments during the meeting, in accordance with the guidelines for FACA committees.
Dr. Landis said she was also pleased with the progress the Committee was making, and noted that the muscular dystrophies present a set of challenges that have made it important for Institutes involved in muscular dystrophy at NIH to work together. She felt these collaborations have been very effective.
Dr. Oster-Granite noted that Dr. Alexander was on travel and not able to be at the meeting, but said that NICHD was pleased to be a part of these efforts.
Dr. Porter, Executive Secretary for the MDCC, reviewed the conflict of interest policies/procedures.
Committee and audience members then were asked to briefly introduced themselves.
II. Senator Paul Wellstone Muscular Dystrophy Collaborative Research Center Progress Report
Dr. Glen Nuckolls gave an update on the Senator Paul Wellstone Muscular Dystrophy Collaborative Research Centers. The current full complement of six Wellstone Centers is funded by NIAMS, NICHD, and NINDS, with each institute supporting two Centers. Each Center supports basic and clinical projects as well as scientific cores.
In 2003, the initial three Centers were established:
The Center at the University of Washington (Seattle, WA) focuses on gene therapy for Duchenne muscular dystrophy (DMD), including the development of adeno-associated viral (AAV) vectors and effective delivery methods for systemic delivery as well as studies on the molecular pathogenesis of myotonic dystrophy. A scientific core at the Center supports vector development. A second core for diagnostic and genetic counseling is supported by the Muscular Dystrophy Association (MDA). Recent data from this Center has demonstrated normal levels of dystrophin expression in all muscles after AAV vector delivery to dystrophic mdx mice.
The Center at the University of Rochester (Rochester, NY ) focuses on understanding the pathophysiology of myotonic dystrophy and facioscapulohumeral muscular dystrophy (FSHD). A clinical trial using Somatokine to treat patients with myotonic dystrophy type 1 is scheduled to begin soon. A core at the center serves as a repository of transgenic mice, human tissue samples, and cell lines for myotonic dystrophy and FSHD. The University of Rochester also houses a registry of myotonic dystrophy and FSHD patients and family members; this is supported by NIH, but not through the Wellstone program. A significant recent finding from this Center is that muscleblind1 knockout mice exhibit a cardiac phenotype similar to that seen in myotonic dystrophy type 1.
The focus of the Center at the University of Pittsburgh (Pittsburgh, PA ) is gene and cell therapy for DMD and limb girdle muscular dystrophy (LGMD). The Center is exploring the potential use of muscle derived stem cell therapies and has core facilities for AAV vector production, dog models of DMD, and biologic imaging. Recent findings from this Center have advanced our understanding of the properties of muscle-derived stem cells and demonstrated effective gene transfer in an animal model of congenital muscular dystrophy.
In 2005, three additional centers were funded:
The Center at the University of Iowa (Iowa City, IA ) is pursuing novel strategies for treatment of DMD and LGMD, including using muscle progenitor cells derived from mouse embryoid bodies. Cores at this Center facilitate the development of diagnostic tools and collection of materials for research.
The Center at the University of Pennsylvania (Philadelphia, PA ) is exploring a strategy to increase muscle mass via inhibition of myostatin or by IGF-1 treatment; blocking muscle degeneration with protease inhibitors is another strategy being pursued. A clinical trial is planned to test safety and feasibility of Bowman-Birk Inhibitor Concentrate (BBIC) in DMD patients. A Core at the Center is working to assess muscular dystrophy mouse models.
The Center at Children’s National Medical Center (Washington DC ) is working to identify genetic modifiers of the natural history of DMD, as well as the response of patients to glucocorticoids. One goal of this Center is to connect the Wellstone network with CINRG network, a clinical trials network run through Children’s. The Center supports a bioinformatics and computing core.
Dr. Nuckolls noted that the activities of the Wellstone Centers are coordinated through a steering committee. He also updated the Committee on some of the new activities connected to the Wellstone Centers. NIH is supporting fellowships at the Centers to support junior investigators and encourage them to pursue collaborations with other Wellstone Centers. The first fellowship has been awarded to a fellow at the University of Washington. NIH is also supporting administrative supplements to the Centers for
focused workshops on high priority topics in muscular dystrophy research. These will be organized as collaborative activities between the Wellstone Centers and investigators outside the Centers.
Dr. Nuckolls mentioned that two Centers have developed websites and the Centers are all working to develop websites with standardized content that describes projects and cores at the Centers.
Colonel Bertram pointed out that there is a lot of overlap between projects funded by the Department of Defense (DOD) and those supported through the Wellstone centers. He suggested that a DOD representative might serve on the Wellstone Center steering committee. He felt this overlap should be addressed and also noted that resource sharing was a critical issue for the field.
Dr. Sharon Hesterlee expressed her concern at the funding level for centers. She felt the amount of funding was not sufficient given the scope of research being conducted by the Centers. She noted that MDA had provided supplements to three of the Centers.
Dr. Porter replied that NIH is carefully monitoring how the Centers are using their funding and also mentioned that NIH is looking for ways to provide additional resources to the Centers; the two new initiatives for supplements are a case in point. Dr. Nuckolls added that the steering committee also provides additional funds for collaborative activities. Dr. Katz pointed out that this level of funding is the largest amount for any Center funded by NIAMS, and also questioned whether it might be better to have more Centers rather than concentrate funding into only a few Centers. He mentioned that it will be important to evaluate whether the Centers are successful. Dr. Cheryl Kitt also pointed out that NIH expects that investigators seek other sources of funding, but cautioned against agencies/organizations funding the same projects. She noted that it is expected that Wellstone investigators will seek additional sources of support.
Mr. Daniel Perez expressed his concern that DMD was the focus of the Wellstone Centers and that other dystrophies were not well represented. A number of Committee members expressed an alternative view, noting that the Wellstone Centers were funded based on scientific opportunity and following an independent peer review of submitted applications; for many of the dystrophies there may be a lack of sufficient knowledge and/or investigators to develop a proposal for a Wellstone Center. In addition, Committee members noted that the infrastructure and shared resources of the Centers could benefit all forms of dystrophy.
III. MDCC Scientific Working Group Report and Introduction to the MD Matrix
Dr. John Porter gave an overview of the process used to develop the Action Plan for the Muscular Dystrophies. He described the process of convening an MDCC Scientific Working Group (MDCC SWG) based on recommendations for SWG participants from MDCC members. The SWG was organized into five different groups, based on the five broad topics in the Research and Education Plan. The SWG met in August 2005 and identified specific research objectives in each of these five areas. Dr. Porter gave examples of some of the research objectives from each of these areas, and highlighted specific advances that preceded the development of these objectives.
Dr. Porter also mentioned the importance of communicating these priorities to the research community, and suggested a publication in a research journal describing the Plan. The Plan will also be posted on the MDCC website. At the next MDCC meeting in Spring 2006, MDCC members will be asked to give an update on their agency or organization’s activities in muscular dystrophy that are relevant to the Plan, as a first step toward implementation. Progress toward Plan objectives – including new initiatives - will be tracked on the MDCC website. Future MDCC meetings will continue to evaluate and assess progress toward goals in the Plan. He then asked MDCC members for their comments on the Plan.
Dr. Hesterlee complimented the NIH and the SWG on the Plan, noting it really went above and beyond the mandate in the MD-CARE Act. She said that MDA does not want to duplicate efforts, and is eager to work along with NIH to implement the objectives in the Plan. Her major concern was that oculopharyngeal muscular dystrophy (OPMD) was not addressed in the Plan. Dr. Porter agreed that this was an omission and will seek expert advice on research accomplishments and goals relevant to OPMD.
Ms. Patricia Furlong was also very pleased with the Plan and complimented the committee on its comprehensiveness. She felt it would be a good way to unite the entire muscular dystrophy scientific and patient community.
Dr. Ed Brann felt the text needed to be expanded in terms of public health aspects of the muscular dystrophies.
Dr. Tingus said he was very impressed with quality of life section of report. He suggested expanding the phrase “cardiovascular care” to include “cardiopulmonary care.” He mentioned that one of NIDRR’s goals is effective communication of evidence based research to community, and that NIDRR would be interested in working to implement some of the goals related to this area.
Dr. Oster-Granite suggested an emphasis on newborn screening; she felt that modification of some of the text would address these NICHD comments. Dr. Brann commented that CDC has a number of ongoing efforts relevant to newborn screening.
Dr. Landis raised the important point that the Plan does not represent absolutely everything that NIH and the muscular dystrophy community will do or fund. If there are areas of research outside the Plan that are important, it may be possible for NIH to fund them. On the other hand, Dr. Katz noted, just because a proposal is responsive to some of the goals of the Plan, does not mean it will necessarily get funded. The standards of peer review will remain in place for all NIH-funded research.
Dr. Katz then outlined the next steps in the process of approving the Plan. He said that Committee members should send their comments and text changes/additions to John Porter within the next week. Changes will be incorporated and the Plan will then be sent out to the Committee via email for a vote.
Mr. Perez felt that Plan was overly focused on DMD research and did not adequately address other forms of muscular dystrophy; other Committee members disagreed and felt that the Plan adequately represented all forms (with the exception of OPMD mentioned previously) given the state of the science for those forms.
A number of Committee members, including Mr. Perez and Dr. Hesterlee, noted that training of physicians was critical to improve the treatment of muscular dystrophy. Doctors need to be better trained in the clinical management of these diseases. Drs. Katz and Landis noted that while this was important, NIH’s role is not to issue treatment guidelines or facilitate training in clinical management; rather NIH supports the research that contributes to these issues. These needs would be best addressed by professional societies/organizations.
IV. Translational Research in Muscular Dystrophy: The Muscular Dystrophy Association (MDA) Translational Research Advisory Committee
Dr. Sharon Hesterlee gave an overview of the MDA’s translational research program. In the Spring of 2003, the MDA Board approved the development of a translational research program. As a first step, MDA formed a Translational Research Advisory Committee (TRAC), which subsequently developed a strategic plan. The Plan identified needs and bottlenecks for academic labs in the drug development process and provided strategies to fill these gaps in preclinical therapy development. MDA currently funds research through this program in four grant categories – Corporate grants, IND Planning Grants, Infrastructure Grants, and Clinical Research Training Grants. Eight grants, funded at a total cost of $8 million, are supported through this program. The two corporate grants represent collaborations between industry and academic researchers and are focused on gene therapy strategies and testing of small molecules in the treatment of muscular dystrophy.
In addition, two meetings have been held under the auspices of this program: a Clinical Research Network Exploratory Meeting in Summer, 2004, and a meeting entitled “Challenges in Drug Development for Muscle Disease: A Stakeholders’ Meeting,” held in Summer, 2005. Dr. Hesterlee noted that a summary of the latter meeting, which explored endpoints and natural history for disease, should be published in Neurology soon.
Dr. Hesterlee also mentioned that the MDA website has a wealth of information regarding resources for translational research.
Both Dr. Landis and Dr. Katz suggested that the MDA’s clinical research training grantees should consider NIH K awards as potential mechanisms of support as well.
V. Translational Research in Muscular Dystrophy: Parent Project Muscular Dystrophy (PPMD) Translational Research
Dr. Lee Sweeney described projects being funded by PPMD aimed at advancing the therapies for DMD. The PPMD uses seed funding to support high risk projects. Strategies include assessing existing treatments for other diseases that could be modified to treat DMD. Research funding is biased toward short term treatment development, with modest investment in long-term strategies. Projects funded to date include gene replacement strategies, RNA manipulation, and new pharmacological agents. A new program, “Project Catalyst” is a joint venture between PPMD and PTC Therapeutics to conduct high throughput screens to identify small molecules as potential drug targets. Specific Phase 1 targets of this project are: Stabilizing IGF-I mRNA, inhibiting translation of myostatin mRNA, increasing utrophin production, increasing production of a7-integrin, and inhibiting translation of phospholambam. Already, one compound, PTC 124, that showed promise in mouse models, was used in Phase 1 safety trials, and will start in Phase 2 trials with DMD patients shortly. Later phases of Project Catalyst will aim to concurrently begin initial chemistry on all five Project Catalyst targets and determine priority of compounds for Phase 3 formulation.
Dr. Sweeney also noted that he and Dr. Eric Hoffman (Children’s Wellstone Center ) will be proposing a workshop of high throughput screening through the Wellstone supplement program.
Dr. Landis noted that molecular libraries are an important part of the NIH Roadmap, and suggested that PPMD and MDA encourage applications relevant to muscular dystrophy through this roadmap initiative.
VI. Translational Research in Muscular Dystrophy: Lessons from NINDS Initiatives
Dr. Story Landis next described the NINDS Translational Research Program. This is a milestone driven program focused on the identification and pre-clinical development of drugs, biologics, and devices in cells and animals, leading to new and effective interventions for any of the neurological disorders. Dr. Landis noted that NINDS was enthusiastic about the possibility of receiving more grants through this program related to muscular dystrophy. She also mentioned that therapeutics development projects supported through this program also includes development of diagnostic techniques as well. She also briefly described another translational research program being utilized by NINDS- the SMA Project – a project to expedite the development of a therapy for SMA. She noted that this strategy was chosen for SMA based on the science behind this disease and the consensus of a single strategy for therapeutic development. For the muscular dystrophies, however, she stressed the importance of pursuing multiple strategies to therapeutic development and also noted that the amount of money invested in the Wellstone Centers exceeds that spent on the SMA Project.
Dr. John Porter mentioned that two grants relevant to muscular dystrophy are funded through the NINDS translational research program, and that two more will be funded soon. He also described a new program at NIH to specifically support translational research in muscular dystrophy. This program announcement will support R21 (exploratory/developmental projects) and U01 (cooperative agreements) projects and include a set aside of $4.5 million over three year ($1.5 million per year). The goal of this program is to encourage studies in a wide range of therapeutic approaches.
Dr. Hesterlee noted that it will be important to advertise this new translational research program, and Dr. Katz said that it is important to organizations like MDA to communicate this program to the research community.
VII. Translational Research in Muscular Dystrophy: The Congressionally Directed Medical Research Program (CDMRP)
Colonel Kenneth Bertram described the projects funded by DoD as a result of Congressional appropriations to the Muscular Dystrophy Research Program. In FY 2003, DoD received a $3.4 million appropriation for the Muscular Dystrophy Research Program and awarded three projects: $1M to Paula Clemens, MD, Children’s Hospital Pittsburgh for a clinical trial of Prednisone vs. Coenzyme Q10 in older Duchenne Muscular Dystrophy (DMD) ; $1M to Eric Hoffman, PhD, Children’s National Medical Center for bioinformatics, data dissemination, and proteomics for muscular dystrophy research; and $1M: Johnny Huard, PhD, Children’s Hospital Pittsburgh for stem cell research in muscular dystrophy. In FY 2004, $50 million was appropriated for the Peer Review Medical Research Program (PRMRP); two awards were made for approximately $3.4M. A $4.25M appropriation was made for the Muscular Dystrophy Research Program and an award was made for a Program Project proposal, “New Advanced Technology for Muscular Dystrophy.” In addition, $1M appropriated to the Muscle Research Consortium, and an award was made to Eric Hoffman, Children’s National Medical Center to support this effort.
In FY 2005, a $3.5M appropriation was made to the Muscle Research Consortium, and an award made for the proposal “Duchenne Muscular Dystrophy Translational Research Program,” to Eric Hoffman, Ph.D. Children’s National Medical Center. This includes a mouse drug screening and testing core. In addition, a $2.5M appropriation was made to the Muscular Dystrophy Research Program; this award is in negotiation.
Following Colonel Bertram’s presentation, a number of comments mentioned concerns that DoD funding is going to well-established and well-funded investigators, perhaps at the exclusion of new investigators and junior faculty. Dr. Hesterlee asked about the process through which these awards are made; Colonel Bertram noted that the DoD receives quite specific guidance from Congress on how to spend the appropriated funds. Dr. Katz reiterated the point that the federal agencies need to coordinate funding of muscular dystrophy projects.
VIII. Scientific Updates
Dr. Rune Frants, an expert in the pathophysiology of FSHD, and Dr. Katherine Wilson, a leading researcher on the nuclear lamina, the structure implicated in Emery-Dreifuss muscular dystrophy (EDMD), were invited to the MDCC meeting to provide updates on research progress in these two muscular dystrophies. Emerging research shows that FSHD and EDMD both target nuclear structures and may share pathogenic mechanisms.
Facioscapulohumeral Muscular Dystrophy
Dr. Frants gave an update on what is known about the pathophysiology of FSHD. He explained the basic genomic mechanism of the contraction of D4Z4 repeat, with the severity of disease inversely proportional to repeat length. Recent findings have begun to elucidate the molecular mechanism underlying FSHD and suggest that a chromatin conformational change mediated by the D4Z4 contraction may play a role. Other research suggests that the disease mechanism may be due to suppression or enhancement of genes downstream of the repeat. A third model suggests a role for nuclear localization in the disease.
Dr. Frants also discussed the form of the disease known as FSHD2, which is the non-chromosome 4-linked form of FSHD. While this form affects only a small subset of patients, he felt that understanding mechanisms underlying this form may provide clues to general mechanisms of FSHD.
A recent publication, currently in press, showed that transgenic mice overexpressing the gene FRG1 display FSHD-like disease. This finding suggests a candidate disease gene and may also open the door to exciting new research approaches to FSHD.
Dr. Frants cited a number of needs in the FSHD research field, including: early and later biomarkers of disease; models of pathogenesis of disease; and infrastructure needs such as multidisciplinary consortia, and international biobanks.
Emery-Dreifuss Muscular Dystrophy
Dr. Wilson described the current state of the science for Emery-Dreifuss muscular dystrophy (EDMD), a member of a class of muscular dystrophies that affect the nucleus. Cell nuclei are surrounded by two concentric membranes, the outer and inner nuclear membranes. Dr. Wilson’s lab focuses on the nuclear lamina, a network of lamin polymers and lamin-binding proteins (e.g.,emerin and BAP) that are embedded in the inner nuclear membrane. The nuclear lamina links the inner nuclear envelope to chromatin, playing key roles in chromatin organization, signal transduction, and gene regulation. EDMD is caused by mutations in the genes that that encode proteins that make up the nuclear envelope, including emerin and lamin A/C, specifically dominant missense mutations in lamin A/C or null missense mutations in emerin. It is thought that one putative disease mechanism may be a loss of mechanotransduction from muscle cytoskeleton to nuclear envelope through the nuclear lamina to chromatin. Mutations in either lamin or emerin result in abnormal nuclear structure and mechanically fragile nuclei and seem to affect a cell’s ability to respond to mechanical stress. The disease selectively affects three tissues-- the heart, major tendons, and skeletal muscles.
Dr Landis asked if there was a single therapeutic strategy for EDMD. It was discussed that emerin may be delivered by gene therapy to emerin-deficient patients and that the laminopathies may be addressed by ridding cells of dominant negative lamin A. Alternatively, several signal transduction pathways are perturbed in EDMD and could be potential targets for pharmacologic interventions.
Dr. Sweeney commented that some EDMD patients have premature stop codons (leading to early truncation of protein synthesis) and that it may be interesting to try the stop codon readthrough drug, PTC124, in these patients.
IX. FSH Society Strategies: Research Grant and Meeting Programs
Mr. Daniel Perez gave an overview of the FSH Society and described the society’s history and mission. One important focus of the Society is the impact of the disease on quality of life. Since its inception, the society has funded $1.3 million through its research grants program. They are able to initiate funding for 4-5 new fellows per year based on money available. Many of the scientific accomplishments and improvements in diagnosis as well as improvements to patients’ lives in recent years have come about as a result of funding from the FSH Society.
The society also has access to approximately 50 family pedigrees, which it can provide to researchers. It does not currently have access to biomaterials from patients.
The FSH Society also works hard to track the FSHD research landscape.
Dr. Wilson commented that the recent advances highlighted by Dr. Frants, including the new FRG1 mouse model of the disease, may help in stimulating the field. Dr. Katz and Dr. Landis stressed that FSHD research is a priority for NIH, and that implementation of the Action Plan would include exploring ways to encourage research in this area.
There were no public comments and the meeting was adjourned at 3:00 PM.
I certify that, to the best of my knowledge, the attachment and above minutes are accurate and complete.
Stephen I. Katz, M.D., Ph.D.
Chairperson, Muscular Dystrophy Coordinating Committee
Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases
February 1, 2006
Kenneth Bertram – CDMRP, Department of Defense
Edward A. Brann - CDC
Dovanon R. Decker – patient advocate
Patricia A. Furlong – Parent Project MD
Stephen I. Katz – NIAMS, NIH, Chair, MDCC
Story C. Landis – NINDS, NIH
Ophelia McLain – Administration on Developmental Disabilities, ACF (on behalf of Pat Morrissey)
MaryLou OsterGranite – NICHD, NIH (on behalf of Duane F. Alexander)
Daniel P. Perez - FSH Society
Steve Tingus – NIDRR, Department of Education
Bradley R. Stephenson – patient advocate
Sharon E. Hesterlee - MDA
Philip H. Sheriden – FDA
John Porter – NINDS, NIH, MDCC Executive Secretary
Other Meeting Participants:
Denis Buxton -- NHLBI, NIH
Holly Campbell –- NINDS, NIH
Wilma Peterman Cross – NIAMS, NIH
Kenyon Daniel -- John Hopkins Medical School
Brian Denger -- PPMD/parent
Morgan Downey -- FSH Society
Ryan Fischer -- PPMD
Rune Frants -- Leiden Univ Medical Center
Kimberly Galberaith -- PPMD
Cheri Gunvalson –- PPMD/parent
Laurie Gutman -- NINDS, NIH
Jim Holaska – John Hopkins Medical School
Robert Jaeger –- NIDRR, Department of Education
Lisa Kaeser – NICHD, NIH
Melissa Kaime –- CDMRP, Department of Defense
Cheryl Kitt -- NIAMS, NIH
Malini Mansharamani -- John Hopkins Medical School
Glenn Nuckolls -- NIAMS, NIH
Vivian Owusu -- NIDRR, Department of Education
Audrey Penn – NINDS, NIH
Sue Perez -- FSH Society
Bill Quirk – Foundation to Eradicate Duchenne / Children’s National Medical Center
Heather Rieff -- NINDS, NIH
Paul Scott -- NINDS, NIH
Susan Sweat – Office of Congressman Roger Wicker
Lee Sweeney – University of Pennsylvania / PPMD
Katie Tifft -- John Hopkins Medical School
Julie Wilberling -- DOD
Katherine Wilson – Johns Hopkins Medical School
Michelle Wozniak– John Hopkins Medical School
Last updated December 27, 2013