Exon skipping: a first in class strategy for Duchenne muscular dystrophy

Abstract

Introduction: Exon skipping is a therapeutic approach for Duchenne muscular dystrophy (DMD) that has been in development for close to two decades. This approach uses antisense oligonucleotides (AONs) to modulate pre-mRNA splicing of dystrophin transcripts to restore the disrupted DMD reading frame. The approach has moved from in vitro proof of concept studies to the clinical trial phase and marketing authorization applications with regulators. The first AON (eteplirsen) has recently received accelerated approval by the Food and Drug Administration in the US. Areas covered: In this review the authors explain the antisense-mediated exon skipping approach, outline how it needs be tailored for different DMD mutation types and describe the challenges and opportunities for each mutation type. The authors summarize the clinical development of antisense-mediated exon 51 skipping, and discuss methods to improve efficiency. Finally, the authors provide their opinion on current developments and identify topics for future prioritization. Expert opinion: Exon skipping development has been a learning experience for all those involved. Aside from an approved therapy, its development has yielded side benefits including the development of tools for clinical trials and has increased collaboration between academics, patients, industry and regulators.