Abstract 16015: Exosome-mediated Reversal of Duchenne Cardiomyopathy

Abstract

Duchenne muscular dystrophy, a crippling genetic disease leading to premature death, affects the heart as well as skeletal muscle. Indeed, cardiomyopathy is the leading cause of death in Duchenne patients. There are no approved treatments for the cardiomyopathy, and novel Duchenne-specific experimental approaches such as exon skipping do not benefit the heart. Here we demonstrate that cardiosphere-derived cells (CDCs), which are in advanced clinical testing for therapeutic regeneration after myocardial infarction, reverse the key pathophysiological hallmarks of Duchenne cardiomyopathy (oxidative stress, inflammation, fibrosis and mitochondrial dysfunction) in mdx mice. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice, and reverse mitochondrial dysfunction in human Duchenne cardiomyocytes. Both CDCs and their exosomes improve heart function in mdx mice (P<0.05); a single injection of CDCs suffices to increase maximal exercise capacity and improve survival (P<0.005). Delivery of a microRNA enriched in CDC exosomes, miR 148a, mimics key effects of CDCs and CDC exosomes. Thus, CDCs effectively treat Duchenne cardiomyopathy, via exosome-mediated transfer of signaling molecules including miR 148a. The present findings motivate clinical testing of CDCs in patients with Duchenne cardiomyopathy.