Researchers developed a new way to improve the efficacy of exon skipping to treat Duchenne muscular dystrophy (DMD), as published in Proceedings of the National Academy of Sciences of the United States of America.

This new approach could treat almost half of DMD cases caused by various mutations in the DMD gene, the authors said. The approach utilizes peptide-conjugated phosphorodiamidate morpholino oligomers (PMOs) to skip exons 45 to 55 in the DMD gene.

To assess the efficacy of their approach, the team of researchers led by Toshifumi Yokota, PhD, from the Department of Medical Genetics at the University of Alberta in Edmonton, Canada conducted experiments using immortalized patient myotubes. The results of these experiments showed that exons 45 to 55 could be skipped by just targeting 5 exons.


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“This study provides proof of concept toward the development of a more economical and effective exons 45 to 55–skipping DMD therapy,” the researchers wrote.

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They also showed that conjugating a cell-penetrating peptide called DG9 to PMOs improved exon 51 skipping. It also ameliorated dystrophin restoration and muscle function in the mouse model of DMD, and when the minimized exon 45 to 55–skipping DG9-PMO was administered locally, dystrophin production was restored.

“We . . . identified DG9 to be a promising, effective cell-penetrating peptide for PMO conjugation for both single-exon and multiexon skipping approaches,” the researchers concluded.

Exon skipping is a promising approach that uses PMOs to convert out-of-frame mutations into in-frame mutations in the DMD gene so that cells can produce a shorter but still partially functional dystrophin protein in patients with DMD.

There are already 4 single-exon skipping treatments that have been approved by the US Food and Drug Administration to treat DMD. However, the efficacy of these treatments is limited and they can only be used to treat 8% to 14% of patients with DMD.

Reference

Lim KRQ, Woo S, Melo D, et al. Development of DG9 peptide-conjugated single- and multi-exon skipping therapies for the treatment of Duchenne muscular dystrophy. PNAS. 2022;119(9):e2112546119. doi:10.1073/pnas.2112546119