Duchenne muscular dystrophy (DMD) is a fatal genetic disease affecting 1 in 3500 boys globally. Despite intensive research over the past three decades, most patients with DMD still die from cardiac failures in their early thirties. 

Built on their previously established gene editing system (TAM, aka CRISPR/dCas9-AID), a research group led by Dr. Xing Chang at Westlake University recently demonstrated that AAV-mediated systemic delivery of TAM could result in efficient exon skipping, substantial restoration of dystrophin (a protein lost in patients with DMD due to genetic mutations), correction of both cardiac and skeletal muscle defects, and extension of lifespan in a newly established DMD murine model. This study has recently been published in Circulation , one of the top medical journals.

In their study, the researchers first established a novel murine model that mimics mutations in the N-terminal actin-binding domain of dystrophin, which account for around 15% of DMD-causing mutations. Unlike widely used mdx mice that present a mild dystrophic pathology, this model recapitulates all the key hallmarks of the progressive pathophysiology of DMD, including significantly shorten lifespan (by around 50%), progressive cardiomyopathy, kyphosis, profound loss of muscle force and myocyte degeneration.

More importantly, the researchers further demonstrated that a single dose systemic delivery of the AAV9-TAM in neonatal DMD mice instituted over 50% targeted exon skipping and restored up to 90% dystrophin in the heart. Despite gradual decline of AAV vector and base editor expression, dystrophin restoration and pathophysiological rescue of muscular dystrophy were long lasted for at least one year. As a result of the extensive dystrophin re-expression, both cardiac and skeletal muscle functions were substantially improved, and the lifespan of the treated animals has been significantly extended. Furthermore, the study further demonstrated that TAM-based in vivo exon skipping elicited minimal double-strand DNA breaks, AAV integration, or other types of RNA splicing in vivo, underscoring the notion that gene editing without direct genome incision is a safer strategy compared to conventional CRISPR-Cas9 system.

This study firmly established that base editing strategy can be robustly applied in vivo to provide therapeutic benefits and extend lifespan. Similar strategies can be applied to other monogenic human diseases that can be corrected by modulating exon skipping/inclusion. Based on this study, a start-up biotech company has been founded to applying novel gene editing technologies for the treatment of human genetic diseases.