Duchenne Muscular Dystrophy (DMD) in both humans and dogs is a fatal, X-linked, recessive muscle disease caused by lack of dystrophin due to deletions or mutations in the dystrophin gene. Adeno- associated virus (AAV)-mediated delivery of micro-dystrophin to skeletal muscle has been successful in mice, however, recent studies indicate that the efficacy of AAV-mediated therapies might be limited by an immune response to viral capsid proteins in humans. By direct intramuscular injection of AAV vectors in wild type and cxmd dogs, we demonstrated robust cellular immune responses to AAV capsid proteins, suggesting the likelihood of cellular immunity to AAV vectors in humans. We further demonstrated that the immune response generated following intramuscular injection of AAV vectors can be averted by a brief course of intense immunosuppression. The broad, long-term objective of this project is to develop AAV- mediated gene therapy strategies in cxmd dogs that can be applied to human patients with DMD. We will test the hypotheses that (1) novel, more effective transient immunosuppression with less toxicity permits sustained transgene expression and subsequent improvement of dystrophic muscle;and (2) that the commonly used AAV serotypes induce a similar immune response. These studies will provide necessary information for future human trials of AAV-mediated gene therapy in humans with Duchenne muscular dystrophy.

Public Health Relevance

The significance of the application is that the methodologies developed in the canine cxmd model can be used to treat human patients with DMD. Gaining a better understanding of the immunogenicity of AAV and developing even better and less toxic immunosuppression regimens will increase the likelihood of achieving the goal of effective gene therapy for human Duchenne muscular dystrophy

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MOSS-H (04))
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Wang, Z; Halbert, C L; Lee, D et al. (2014) Elimination of contaminating cap genes in AAV vector virions reduces immune responses and improves transgene expression in a canine gene therapy model. Gene Ther 21:363-70
Kerwin, William S; Naumova, Anna; Storb, Rainer et al. (2013) Mapping contrast agent uptake and retention in MRI studies of myocardial perfusion: case control study of dogs with Duchenne muscular dystrophy. Int J Cardiovasc Imaging 29:819-26
Wang, Zejing; Storb, Rainer; Tapscott, Stephen J et al. (2012) Analyzing cellular immunity to AAV in a canine model using ELISPOT assay. Methods Mol Biol 792:65-74
Wang, Zejing; Storb, Rainer; Halbert, Christine L et al. (2012) Successful regional delivery and long-term expression of a dystrophin gene in canine muscular dystrophy: a preclinical model for human therapies. Mol Ther 20:1501-7
Wang, Zejing; Tapscott, Stephen J; Chamberlain, Jeffrey S et al. (2011) Immunity and AAV-Mediated Gene Therapy for Muscular Dystrophies in Large Animal Models and Human Trials. Front Microbiol 2:201
Arnett, Andrea L H; Garikipati, Dilip; Wang, Zejing et al. (2011) Immune Responses to rAAV6: The Influence of Canine Parvovirus Vaccination and Neonatal Administration of Viral Vector. Front Microbiol 2:220
Wang, Zejing; Tapscott, Stephen J; Storb, Rainer (2011) Local gene delivery and methods to control immune responses in muscles of normal and dystrophic dogs. Methods Mol Biol 709:265-75
Wang, Zejing; Storb, Rainer; Lee, Donghoon et al. (2010) Immune responses to AAV in canine muscle monitored by cellular assays and noninvasive imaging. Mol Ther 18:617-24
Halbert, Christine L; Madtes, David K; Vaughan, Andrew E et al. (2010) Expression of human alpha1-antitrypsin in mice and dogs following AAV6 vector-mediated gene transfer to the lungs. Mol Ther 18:1165-72