Abstract:
Duchenne muscular dystrophy (DMD) is a progressive and ultimately fatal muscular dystrophy caused by mutations in the dystrophin (DMD) gene1,2. Currently there is no cure for DMD, however recent work using AAV-CRISPR-Cas9 based technology has yielded varying degrees of success in restoring dystrophin protein expression3-5. However, these methods of gene therapy are limited by the inherent risks and hurdles associated with viral vector-based gene therapy. Here we utilized allogeneic bioengineered exosomes, a genetic therapy method that circumvents all the hurdles associated with traditional viral vector-based gene therapy, to deliver full-length human dystrophin (DMD) mRNA to mdx mice. Exosome-DMD mRNA therapy restored dystrophin protein expression in fast- and slow-twitch skeletal muscle, diaphragm, and heart, lowered serum creatine kinase, improved grip strength deficits, and had no toxicity in mdx mice. Furthermore, dystrophic muscle markers including necrosis and centralized myonuclei were almost normalized to wild-type levels in the exosome-DMD mRNA treated mdx mice. Similar to our in vivo murine observations, we restored dystrophin protein expression in DMD patient fibroblasts with exosome-DMD mRNA. Our data establish that exosome-DMD mRNA is a promising therapy for treating patients with DMD. We anticipate that bioengineered exosomes can be used successfully to treat a plethora of other diseases of genetic etiology.
