Potential therapies now entering clinical trials for treatment of Duchenne Muscular Dystrophy include microdystrophin gene transfer (resulting in an internally truncated dystrophin) and suppression of nonsense mutations (resulting in a full-length dystrophin). In recently completed human trials of each, we have identified significant T-cell immune responses directed at dystrophin epitopes in both treated and untreated patients. It is the overall goal of our Wellstone Muscular Dystrophy Cooperative Research Center to identify the prevalence and molecular determinants of this immunity, and to determine what role immune responses to both dystrophin and recombinant AAV may play in the success or failure of gene correction therapies. In pursuit of this goal, we propose a plan that makes use of the extensive expertise and resources of the Centers for Gene Therapy and for Vaccines and Immunity at NCH. In Project 1 (J. R.Mendell, PI), we will characterize the properties and prevalence of dystrophin-specific T-cells in DMD subjects;determine the effect of initiation of glucocorticoid therapy on modulating this response;and assess these responses in a pilot trial of vascular delivery of an AAV8.MCK.micro-dystrophin. In Project 2 (C. Walker, PI), we will assess enhancement of transgene delivery in AAV-immune individuals via transient depletion of serum neutralizing antibodies;define the role the role of CD4-I- and/or CD8+ T cells against a foreign transgene product in clearance of rAAV-transduced myocytes;and determine if transient blockade of T cell activation and expansion facilitates persistent expression of a non-self transgene. The Administrative Core (Core A;J. Mendell, PI) makes use of a cadre of staff with experience in managing collaborative trials and projects in DMD, including first-in-man trials of gene therapy. The Histopathology Core (Core C;Z. Sahenk, PI) will utilize expert staff to provide resources for the analysis of tissue from projects within this and other Weilstone Centers. The Immunology Scientific Core (Core C;C. Walker, PI) will deploy cutting-edge assays for the elucidation of T-cell function, and provide a unique resource among the Wellstone network. The Education Core (Core D;P. Martin, PI) will build upon nationally recognized graduate and post-graduate programs to provide a unique educational environment.

Public Health Relevance

The characterization of immunity to dystrophin (both pre- and post-treatment) has immediate implications for the design of therapies and for monitoring safety in clinical trials. The feasibility of widespread AAV-mediated gene delivery requires an understanding of immune responses within muscle. Testing potential therapeutic targets to combat immunity expands gene correction to a broader population of affected Individuals.

Agency
National Institute of Health (NIH)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD066409-05
Application #
8685775
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Urv, Tiina K
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43205
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