The Administrative Core (J. Mendell, PI) will provide scientific and fiscal oversight of and direction to the MDCRC Program. The Core will build upon the existing expertise of the Neuromuscular Clinical Research Program at the Research Institute at Nationwide Children’s Hospital (NCH). The translational research staff already assembled by the PI, Dr. Mendell, has a demonstrated expertise in designing and implementing cutting-edge clinical research projects. The staff’s experience in coordinating large multi-center collaborative programs is directly relevant to administration of a Wellstone MDCRC, and includes experience in coordination of communication among multiple sites; quality control and document tracking; data management; data mining and reporting; milestone and task management; and fiscal accountability. Access to patients will be facilitated by the United Dystrophinopathy Project, a large NIH-funded multicenter genotype/phenotype and natural history consortium directed by Dr. Kevin Flanigan, who has recently joined the NCH Center for Gene Therapy. Dr. Mendell has extensive experience in the design and performance of DMD clinical trials, including unique experience in the performance of gene transfer trials, and both he and Dr. Flanigan have served as consultants for the design of trials of gene transfer or gene correction (exon skipping and nonsense suppression) trials that are currently underway.
The Core will be responsible for establishing and maintaining effective communications and cooperation among investigators both inside the NCH MDCRC and among the wider Wellstone network. In this role, it will develop clear internal and external procedures for monitoring and evaluating the research projects and core facilities; establish mechanisms for managing and sharing data, animal models, and other resources among investigators; and provide administrative support for the development of both extramural funded and industry-sponsored translational research projects, and for the Educational Core activities of the MDCRC. The Administrative Core will also establish a Center Advisory Committee, and develop the framework to ensure the contribution of this Committee to the oversight of the Center’s research and translational activities.
The human immune system presents a potentially serious barrier to treatment of Duchenne muscular dystrophy (DMD). Pre-existing T cell immunity to dystrophin has been observed in patients with DMD. Moreover, in subjects with large deletions in the dystrophin gene, sequences that are unique to a therapeutic dystrophin transgene can prime T cell immunity. Further complicating the picture are humoral and cellular immune responses to the AAV capsid that have the potential to interfere with vector-mediated transduction of muscle. This MDCRC Center is structured to provide insight into cellular immune responses to dystrophin or AAV capsid proteins in DMD patients who are candidates for therapies that include gene replacement, exon skipping, and stop codon suppression. The Immunology Core has two objectives that support this Center. The first is to provide access to well established assays for standardized quantification of T cell responses to dystrophin and AAV capsid proteins in human subjects with DMD. The second objective is to adapt advanced technologies for monitoring immunity to the study of DMD. This includes methods for direct visualization of dystrophin-specific T cell responses in human subjects to assess their function in target tissues like muscle.
The Histopathology Core will perform a vital function in Paul D. Wellstone MDCRC. The director of the core is an experienced muscle pathologist (Z. Sahenk, MD, Ph.D, Director of the Histopathology Laboratory at Nationwide Children’s Hospital). Project 1 will require analysis of muscle tissue taken directly from DMD patients. In Aim 1 of Project 1, T cell infiltration will be examined as an expression of a pre-existing immune response to dystrophin. In addition, sequencing of the DMD mRNA will be performed, in order to assess the relationship between altered splicing and antigenic dystrophin epitopes. In Aim 2 of Project 1, specific T cell immunity will be studied before and after corticosteroid treatment. Aim 3 of Project 1 closely scrutinizes gene expression and immune response following AAV-micro-dystrophin delivery to muscle. In Project 2 emphasis switches to an experimental paradigm using the rhesus macaque. This too is familiar territory to this laboratory because tissue from this animal model has been processed in this laboratory for the past several years. In Aim 1 of project 1 AAV.micro-dystrophin gene delivery will be examined after depleting neutralizing antibodies to study the role of T cell immunity to viral capsid. In Aim 2 of project 2 tissue sections will be used to help define the role of CD4+ and CD8+ T cells against a foreign transgene product. In the final Aim 3 of Project 2 similar tissue studies will be necessary to understand the role of possible immunosuppressant agents. In the course of study of both human and non-human primate tissue, histologic sections will employ standard stains and immunohistochemistry for gene expression and immunological markers for T cell subsets, and western blots similar to every day studies in this laboratory.
The Training and Education Core has three goals:
1. To support a specialized training program for a pre-doctoral and a post-doctoral trainee
2. To support outreach for education of patients and their families
3. To update physicians in muscular dystrophy research and patient care
The core is lead by Paul Martin, PhD, and participating faculty members are experienced clinicians and basic scientists intensively involved in education with a history of collaborative interactions. The training pool is composed of a comprehensive set of high-caliber clinical programs and Ph.D. graduate programs at the Ohio State University and Nationwide Children’s Hospital.
The pre-doctoral and postdoctoral trainees actively participate in a research project aligned with the translational goals of the MDCRC. Clinically-based trainees attend the muscular dystrophy clinic and ancillary clinics. Participation in studies that foster translational research and instruction in the responsible conduct of research are required for all trainees supported by this core.
This cross-discipline training model is further enriched for all pre-doctoral and postdoctoral trainees and junior faculty by support of the ongoing Nationwide Children’s Hospital and OSU Muscle Study Group. Center participants are also actively involved in educating patients, their families, local physicians and high school students about research advances in muscular dystrophy. This core therefore provides comprehensive training required to foster the careers of future generations of clinicians and scientists in the field of muscular dystrophy. Interested pre-doctoral and post-doctoral candidates are encouraged to contact Dr. Martin.
As part of its outreach and education efforts, the Core sponsors:
A seminar series at Nationwide Children’s Hospital, with speakers from the national and international muscular dystrophy communities.
A monthly podcast – This Month in Muscular Dystrophy – covering current topics in muscular dystrophy research and patient care.
A family newsletter for muscular dystrophy patients
A yearly family patient conference
A regional muscular dystrophy physician’s conference