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.
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
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