Addressing Shortcomings of AAV GeneTherapies for the Muscular Dystrophies

University Of Florida, Gainesville FL

Investigators

Abstract

Abstract This Wellstone Muscular Dystrophy Specialized Research Center is focused on optimizing AAV-mediated gene therapies for Duchenne and Limb Girdle Muscular Dystrophy. We are developing novel approaches to address deficiencies we have identified in the existing human AAV-gene therapies for the muscular dystrophies. Our first goal (Project 1) is to design and optimize miniaturized utrophin-dystrophin chimeric transgenes that can be delivered using a single AAV vector to the skeletal muscles and hearts of animal models of DMD, the human iPSC-derived engineered heart tissues of Project 2, and eventually to humans. Secondly, we will work to design and test improved AAV capsids and transgenes in collaboration with Project 2 with the goal to reduce immunostimulatory activity. Project 2 will design and test AAV gene therapy for sarcoglycan deficiency. These include the design and optimization of AAV-gene therapy vectors for SGCG-LGMD with enhanced transgene expression and stability, and reduced immunostimulatory activity. Project 2 will evaluate the optimized AAV- SGCG vectors in vivo and demonstrate functional restoration in heart and muscle. Lastly, Project 2 will test AAV- transgenes from Projects 1 and 2 in a humanized mouse model of anti-AAV immunity for chemokine stimulation, liver toxicity, and T cell mediated capsid responses. Project 3 entails a clinical study that will follow the skeletal and cardiac muscle progression of micro-dystrophin treated boys and sarcoglycan-deficient individuals using non-invasive biomarkers and functional outcomes. These projects will work together for the common goal of improving the safety and efficacy of gene therapies for muscular dystrophies, directly comparing data across Projects to ascertain transgene-specific and platform-related results. Project 3 will collaborate with Project 1 to perform tissue validation of T1/T2 measures with tissue histology in the dystrophic rat (MDR). Project 3 will also work with Project 1 to characterize the MR response to AAV therapy and assess blood flow in muscles pre- and post-AAV treatment. Project 3 will collaborate with Project 2 to provide blood samples that correlate with imaging data. The Center will continue to make important contributions to sharing resources, maintaining our Shared Resource Core for all muscular dystrophy researchers. We will also expand our successful training efforts, continue to cultivate our collaborations with patient advocacy groups and industry, and maintain our outreach efforts for the muscular dystrophy community.