Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive genetic disorders caused by mutations in the dystrophin gene. Numerous approaches have been explored to treat DMD, but methods to replace the dystrophin gene in muscle are the most direct approach to circumventing the primary cause of the disorder. In previous cycles of this project we developed dystrophin expression cassettes, characterized numerous mouse models for DMD, explored the replacement parameters needed for therapy, developed mini- and micro-dystrophins and showed that AAV vectors could be used for systemic gene delivery to muscles of adult mammals. Together with colleagues in Seattle we are beginning to develop clinical approaches for DMD gene therapy. An effective gene therapy for this disorder will require methods for systemic gene delivery to limb, cardiac and respiratory muscle of patients. Developing and testing such methods is the focus of this renewal application. We propose studies using tagged versions of our best micro-dystrophin clones to address critical parameters related to systemic delivery methods in large animal models as a prelude to human application.
In Aim 1 we will refine a novel vascular delivery method for AAV delivery to limb muscles that incorporates standard dialysis equipment into a recirculating system to preserve tissue integrity by maintaining a metabolic balance with supplemental oxygen delivery; the repeated and prolonged exposure to targeted muscles greatly enhancing vector uptake.
In Aim 2 venous and arterial delivery systems able to target muscles of the forelimb, heart and diaphragm will be explored and contrasted with hind limb muscle delivery.
In Aim 3 the optimized methods will be combined to deliver dystrophin to all the major muscle groups needed for effective therapy and increased lifespan: limb, heart and respiratory muscles. Together these studies should facilitate development of clinical trials for DMD involving systemic, whole body treatment targeting the critical muscle groups that affect patient quality of life and lifespan. Significant advantages of this approach are that AAV delivery of micro-dystrophin could be used to treat all DMD/BMD patients regardless of their mutation, it would enable therapy in heart and diaphragm and not just limb muscles, and these AAV delivery methods should be applicable to a wide variety of other muscular dystrophies and disorders of muscle.
Gene therapy has tremendous potential to treat Duchenne and Becker muscular dystrophies by addressing the direct cause of the disorder: a defective dystrophin gene. This project is focused on pre-clinical testing of gene therapy methods that have proven effective in rodent models of DMD.
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