Mutation-Based Therapy for Duchenne Muscular Dystrophy: Antisense Treatment Arrives in the Clinic.

Abstract

Duchenne muscular dystrophy (DMD) arises from mutations in the dystrophin gene. The dystrophin gene is composed of 79 exons, and the majority of mutations in DMD are deletions, often spanning multiple exons.1 In 2016, the US Food and Drug Administration (FDA) granted accelerated approval for eteplirsen (Exondys51), an antisense oligonucleotide compound designed to block exon 51 of dystrophin to restore the reading frame in patients with DMD with specific mutations (Figure, A).2 This treatment is directed at ≈10% to 15% of patients with DMD (≈1500 treatment-eligible individuals). The approval of eteplirsen is game changing for the field of molecular gene correction. However, its approval was viewed as controversial because of the unconventional clinical trial data and limited efficacy. Figure. Eteplirsen (Exondys51)-mediated reading-frame correction of Duchenne muscular dystrophy (DMD) mutations. A, Top , Schematic of the dystrophin protein and its domains. ABD1 indicates actin binding domain; CR, cysteine rich domain; CT, C-terminal domain; and H, hinge regions. The spectrin-like repeats are numbered. The red bar indicates the approximate exon 51 targeting region. Middle , Schematic showing eteplirsen-mediated reading-frame correction of a DMD frameshift mutation. The normal dystrophin locus from exons 41 to 52 is shown, indicating the reading frame of each exon. Many patients with DMD have variable-sized deletions spanning exons 47 to 50, disrupting the reading frame (dashed blue line). Eteplirsen (red box) is an antisense oligonucleotide that binds to exon-splicing enhancer sequences in exon 51, causing its exclusion from mRNA. Because exon 51 is excluded, exons 46 (or 47, 48, and 49) joins to exon 52 (solid blue line) to restore an open reading frame. B , Antisense oligonucleotides have complementary sequences to those within an exon, in this case exon 51. Chemical modifications to the antisense oligonucleotides permit the double-stranded hybrid …