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 vi^ith 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 MD-CRC 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 the proposed 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 and to assess their function in target tissues like muscle.

Public Health Relevance

The Immunology Core is designed to provide standardized, reproducible analysis of cellular immune responses to dystrophin humans with Duchenne Muscular Dystrophy (DMD). Facilitating the analysis of immunity in Projects 1 and 2 has considerable relevance to treatment of progressive muscular disease associated caused by DMD.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZNS1-SRB-S)
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Nationwide Children's Hospital
United States
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Mendell, Jerry R; Sahenk, Zarife; Malik, Vinod et al. (2015) A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol Ther 23:192-201
Chicoine, L G; Montgomery, C L; Bremer, W G et al. (2014) Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol Ther 22:338-47
Flanigan, Kevin M; Campbell, Katie; Viollet, Laurence et al. (2013) Anti-dystrophin T cell responses in Duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect. Hum Gene Ther 24:797-806
Heller, Kristin N; Montgomery, Chrystal L; Janssen, Paul Ml et al. (2013) AAV-mediated overexpression of human ?7 integrin leads to histological and functional improvement in dystrophic mice. Mol Ther 21:520-5
Mendell, Jerry R; Lloyd-Puryear, Michele (2013) Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy. Muscle Nerve 48:21-6
Mendell, Jerry R; Shilling, Chris; Leslie, Nancy D et al. (2012) Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol 71:304-13