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 Ca 2+ -handling by forced expression of SERCA2a in cardiomyocytes mitigates heart failure and arrhythmogenesis in a pig model for Duchenne muscular dystrophy (DMD). 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 voltage amplitude and sudden cardiac death with a lifespan of usually less than 4 months. Slow antegrade intracoronary infusion of AAV1.SERCA2a (3×10 13 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 DMD Δ52 to DMD Δ51-52, 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, 3×10 13 vg/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.