Preclinical development of genome editing to treat Duchenne muscular dystrophy by exon skipping.

Abstract

Duchenne muscular dystrophy (DMD) is caused by loss-of-function mutations to the gene encoding dystrophin. Restoring the reading frame of dystrophin by removing internal out-of-frame exons may address symptoms of DMD. Therefore, the principle of exon skipping has been at the center stage in drug development for Duchenne muscular dystrophy (DMD) over the past two decades. Antisense oligonucleotides (AONs) have proven effective in modulating splicing sites for exon skipping, resulting in the FDA approval of several drugs using this technique in recent years. However, due to the temporary nature of AON, researchers are actively exploring genome editing as a potential long-term, single-administration treatment. The advancements in genome-editing technology over the last decade have boosted this transition. While no clinical trials for exon skipping in DMD via genome editing have been conducted as of this writing, preclinical studies show encouraging results. This review describes the preclinical landscape of genome editing for exon skipping in DMD treatment. Along with highlighting the adaptability of genome editing in exon skipping, this review also describes delivery challenges and outlines future research directions that could set a new stage for enhanced therapeutic development in DMD.