Antisense-mediated exon skipping for duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe, progressive neuromuscular disease for which there is currently no cure available. The disease is caused by mutations in the dystrophin-encoding DMD gene that disrupt the open reading frame and completely abolish dystrophin function. Antisense-mediated exon skipping is a promising approach that is close to clinical application. It aims to modulate pre-mRNA splicing such that the reading frame is restored, allowing for the generation of partly functional dystrophin proteins, as found in less severe Becker muscular dystrophy. Proof-of-principle for this approach has been obtained in patient-derived cell cultures and animal models carrying different types of mutations (deletions, duplications, small mutations and splicing mutations). In theory this approach should be applicable to almost 80% of all patients, but as different exons need to be skipped to restore various mutations, skipping a single exon is beneficial to a subset of patients. All DMD exons can currently be skipped and antisense oligonucleotides to induce exon 51 skipping (applicable to the largest group (13%) of patients) are in the early phase of clinical trials.