Project 1 - Sweeney_Hammers

ABSTRACT The multifaceted pathologies associated with muscular dystrophies, particularly Duchenne muscular dystrophy (DMD), represent major challenges to the development and clinical implementation of effective therapeutics for these diseases. AAV gene therapies delivering micro-dystrophin transgenes to all striated muscles are now in the clinic, with hopes of bringing transformative outcomes course of DMD disease. However, much work is still needed to advance the safety and efficacy of these therapies before widespread implementation for the treatment of DMD. In the clinic, there have been serious and fatal responses to viral capsids and the expressed transgenes. Furthermore, we have found that certain micro-dystrophin designs can hasten onset of lethal cardiomyopathy in mice. The goal of the current project is to develop next-generation AAV gene therapies for DMD that a) avoid transgene safety concerns and b) reduce the immune response to vector delivery, thereby advancing the path to safe, effective, and broad-use AAV gene therapies for muscular dystrophies. In Aim 1, we will develop novel utrophin-dystrophin chimeric transgenes that are less immunogenic than their micro- dystrophin counterparts. Aim 2 seeks to improve the design AAV capsids and vector genomes to reduce risks of provoking severe immune responses during treatment. It is anticipated that progress towards these aims will significant advancements towards safe and efficacious implementation of gene therapy for DMD and other muscular dystrophies.