Raising hopes for treatment of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy represents the most frequent hereditary childhood myopathy, leading to progressive muscle degeneration and weakness, and to premature death due to respiratory and cardiac failure. The X-chromosomal location of the mutant gene encoding dystrophin (DMD) renders 1 in 3,500 to 5,000 male newborns affected (1). The vast majority of patients carry frameshift mutations in DMD, which are mainly exon deletions (2). Antisense oligonucleotide-mediated exon skipping aimed at reframing DMD transcripts has already been translated into clinical trials (3, 4). Moreover, intravenous application of AAV9 delivering CRISPR/Cas9 components in a beagle model of DMD (exon 50 deficiency) proved successful in restoring expression of a shortened dystrophin in various muscles, including the heart (5). However, functional data were not reported previously. In a paper published in Nature Medicine by scientists from Munich, pigs of a transgenic strain lacking dystrophin exon 52 were studied with regard to skeletal muscle function and electrophysiological stability of the heart. The authors demonstrate that the systemic infusion of AAV9-Crispr-Cas9 combined with appropriate guide RNAs is sufficient to express a shortened but stable dystrophin in striated muscles, including the diaphragm and the heart. A large area of vulnerable myocardium was revealed by high-resolution electrophysiological mapping in the diseased pigs, which died of sudden cardiac death no later than 105 days after birth. Importantly, the vulnerable area was reduced by AAV9-Cas9-gRNA treatment, significantly extending lifespan of the treatment group. Additionally, human iPS-derived cardiomyocytes subjected to analogous AAV6-Cas9-gRNA transduction demonstrated dystrophin expression and normalization of calcium handling. These findings are exciting as they show in a large preclinical animal model and in human iPSC-derived cardiac cell systems that gene editing by Crispr-Cas9 is capable of inducing dystrophin expression and improving heart and skeletal muscle functions in Duchenne muscular dystrophy.