Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy

Significance Duchenne muscular dystrophy (DMD) is a lethal genetic disorder caused by a lack of dystrophin protein. Cardiomyopathy is a leading cause of death in DMD. Although exon skipping with antisense morpholino oligonucleotides is very promising, morpholino-mediated exon skipping has induced barely detectable dystrophin levels in the hearts of DMD animal models. Here, we show that systemic multiexon skipping using a cocktail of peptide-conjugated morpholinos (PPMOs) rescued dystrophin expression in the myocardium and cardiac Purkinje fibers in a dystrophic dog model. The treatment reduced vacuole degeneration in Purkinje fibers and improved electrocardiogram abnormalities without apparent toxicity. These results indicate that PPMO-mediated multiexon skipping is a therapeutic approach for treating cardiac conduction abnormalities in DMD.