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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.

Duchenne muscular dystrophy (DMD) is a fatal, X-linked recessive disorder characterized by progressive muscle loss and cardiorespiratory complications. Mutations in the DMD gene that eliminate the production of dystrophin protein are the underlying causes of DMD. Viltolarsen is a drug of phosphorodiamidate morpholino oligomer (PMO) chemistry, designed to skip exon 53 of the DMD gene. It aims to produce truncated but partially functional dystrophin in DMD patients and restore muscle function. Based on a preclinical study showing the ability of antisense PMOs targeting the DMD gene to improve muscle function in a large animal model, viltolarsen was developed by Nippon Shinyaku and the National Center of Neurology and Psychiatry in Japan. Following clinical trials conducted in Japan, Canada, and the United States showing significant improvements in muscle function, viltolarsen was approved for medical use in Japan in March 2020 and the United States in August 2020, respectively. Viltolarsen is a mutation-specific drug and will work for 8% of the persons with DMD who carry mutations amenable to exon 53 skipping. This review summarizes the pharmacological profile of viltolarsen, important clinical trials, and challenges, focusing on the contribution of Japanese patients and researchers in its development.

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