Development of DG9 peptide-conjugated single- and multi-exon skipping therapies for the treatment of Duchenne muscular dystrophy

Abstract

Significance Duchenne muscular dystrophy (DMD) is a fatal disorder of progressive body-wide muscle weakness, considered the most common muscular dystrophy worldwide. Most patients have out-of-frame deletions in the DMD gene, leading to dystrophin absence in muscle. There is no cure for DMD, but exon skipping is emerging as a potential therapy that uses antisense oligonucleotides to convert out-of-frame to in-frame mutations, enabling the production of truncated, partially functional dystrophin. Currently approved exon skipping therapies, however, have limited applicability and efficacy. Here, we developed a more economical approach to skip DMD exons 45 to 55 (a strategy that could treat nearly half of all DMD patients) and identified DG9 peptide conjugation as a powerful way to improve exon skipping efficiencies in vivo.