Development of DG9 peptide-conjugated single- and multi-exon skipping therapies for the treatment of Duchenne muscular dystrophy
Kenji Rowel Q. Lim, Stanley Woo, Dyanna Melo, Yiqing Huang, Kasia Dzierlega, Md Nur Ahad Shah, Tejal Aslesh, Rohini Roy Roshmi, Yusuke Echigoya, Rika Maruyama, Hong M. Moulton, Toshifumi Yokota
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.