Project 2 (CT GalNAc transferase gene therapy for DMD) seeks to translate well-documented proof of principle studies showing this transgene can inhibit muscular dystrophy to treat skeletal muscles of the lower limb via a localized vascular delivery protocol. Preliminary studies are provided showing that this transgene can inhibit the development of disease both in the mdx model of Duchenne muscular dystrophy (DMD) and for the dyW model of Congenital muscular dystrophy 1A (MDC1 A). This grant will provide proof of principle data using localized intravascular delivery of the rAAVS (rh.74)-CT GalNAc transferase to lower limb muscles through perfusion of the femoral artery. This localized vascular delivery protocol will be facilitated by the use of an AAV serotype best suited for this purpose and use of a muscle-specific promoter to insure tissue-specific expression.
Aim 1 will provide proof of principle data in the mdx mouse, a model for DMD, demonstrating inhibition of skeletal muscle pathology and functional correction of muscle physiology.
Aim 2 will demonstrate the localized vascular delivery protocol to be used in the proposed clinical trial is safe and effective in the non-human primate, and provide necessary data on biodistribution, pharm/tox, and localized transgene expression.
This Aim will also address potential barriers to success, such as immune response to the viral capsid and transgene as well as potential inhibition by neutralizing antibodies. These data will provide the proof of principle evidence of clinical efficacy and safety required to bring this therapy to a pre- IND meeting with the FDA, with the goal of developing a therapeutic for regional vascular delivery in the limb.
Aim 3 involves all aspects of this application process.
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