The Implications of Dystrophin-Speclfic T cells for DMD Gene Correction Proof-of-principle studies in mouse and dog models of Ducheime muscular dystrophy (DMD) have established that gene replacement therapy is a promising treatment strategy. Attempts to apply the tenets learned from pre-clinical to clinical protocols did not predict dystrophin-specific T cells targeting novel epitopes on muscle fibers downstream of the mutation. In one case these were expressed on revertant fibers, a finding contrary to the axiom that forecasts a tolerizing role for these fibers. Another treatment paradigm, gentamicin-induced mutation suppression, proved equally confounding because dystrophin-specific T cells were isolated fi-om the blood and muscle following treatment. These observations require further study to achieve success in gene correction strategies for DMD.
In Aim 1 we will characterize the properties of dystrophin-specific T cells in the blood and muscle of DMD patients with well characterized mutations to determine how many patients exhibit cellular immunity to dystrophin and define the location of cognate selfepitopes within the mutated dystrophin protein. We will examine the effector fimctions of CD4+ and CD8+ T cells that are dystrophin specific.
In Aim 2 we will look specifically at the role of glucocorticoids in modulating T cell response in a designated three-month treatment program of naive subjects. Here we anticipate a T cell phenotype change fi-om effector/inflammatory to a regulatory/suppressor role.
In Aim 3 we will perform a vascular delivery clinical gene transfer study using AAVS.MCK.micro-dystrophin. We can achieve high levels of muscle fiber transduction through vascular delivery of transgene to specific leg muscles in the rhesus macaque. This sets the stage for clinical efficacy. The study inclusion criteria include currently identified immune barriers based on prior experience and will add findings that emerge from Projects 1 and 2.

Public Health Relevance

Finding a treatment for Duchenne muscular dystrophy through gene correction strategies is a major research goal that has been confounded by the immime system. This project targets important questions related to: 1) immunological barriers to successful gene correction;2) addresses the interface of the immune system with glucocorticoid treatment, the only known effective treatment for the disease;and 3) tests the potential for overcoming immune barriers that are known and will be ascertained during this project to achieve successful gene replacement therapy through vascular delivery.

National Institute of Health (NIH)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZNS1)
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Nationwide Children's Hospital
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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