Gene Therapy for Cardiomyopathy associated with Duchenne Muscular Dystrophy in a Pig Model

Background: Genetic cardiomyopathies caused by mutations in the dystrophin gene (DMD) are only partially responsive to current pharmacological heart failure treatments, although dilated and arrhythomogenic phenotypes of cardiomyopathy are frequent. Objective: In this study, we tested whether a normalization of Ca2+-handling by forced expression of SERCA2a in cardiomyocytes mitigates heart failure and arrhythmogenesis in a pig model for Duchenne muscular dystrophy (DMD) in pigs. Methods and results: Male offspring of pigs lacking DMD exon 52 are characterized by heart failure with reduced ejection fraction (HFrEF, EF 34.5±1.8% vs. 49.2±1.0% in control hearts), arrhythmogenesis due to large apical regions of reduced action potential (AP) amplitude and sudden cardiac death with a lifespan of usually less than 4 months. Slow antegrade intracoronary infusion of AAV1.SERCA2a (3x1013 virus genomes (vg) per pig) improved left ventricular ejection fraction (EF 47.3±2.0%, p<0.05) to a similar extent as germline editing of DMDΔ52 to DMDΔ51-52, inducing a Becker dystrophy (BMD) genotype (EF 46.7±3.8%). Moreover, AAV.Serca2a significantly reduced myocardial inflammation and fibrosis and areas of reduced AP amplitude. Conclusions: In DMD pigs, 3x1013vg/heart of GMP-grade AAV1.SERCA2a sufficed to normalize left ventricular function, and improved electrical vulnerability of the heart. Hence, AAV.SERCA2a may serve as a treatment option for DMD cardiomyopathy. ### Competing Interest Statement RJH is a scientific cofounder of Asklepios and Sardocor, companies engaged in commercializing gene therapy of heart failure and cardiomyopathies CK and WW hold IP for a DMD gene editing therapy