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Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy

Gene Therapy volume 27, pages 407–416 (2020)Cite this article

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Abstract

Duchenne muscular dystrophy (DMD) is one of the most common lethal muscle-wasting disorders affecting young boys caused by mutations in the DMD gene. Exon skipping has emerged as a promising therapy for DMD. Antisense oligonucleotides (AONs) are designed to induce the skipping of exon(s), in order to restore the reading frame, and therefore, allow for dystrophin expression. Eteplirsen and golodirsen, AONs for DMD exons 51 and 53 skipping, have been recently approved by the FDA. Viltolarsen, an AON for DMD exon 53 skipping, was approved in Japan earlier this year. Although promising, the efficacy of eteplirsen and AON sequence employed remain controversial. In addition, exon skipping faces challenges including the applicability and delivery. This article reviews and discusses exon skipping and the current advances being made in the field, on drugs, multi-exon skipping, sequence design, and applicability. We also discuss challenges and future directions that will facilitate the development of exon skipping therapy.

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Fig. 1: Illustration of the mechanism of exon skipping therapy, restoring dystrophin expression by the skipping of exon 52.
Fig. 2: Comparison of AONs for skipping of exons 51 and 53 in the DMD.

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Acknowledgements

This work was supported by Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research (CIHR), Alberta Innovates: Health Solutions (AIHS), Jesse’s Journey, Canada Foundation for Innovation (CFI), Alberta Advanced Education and Technology, and the Women and Children’s Health Research Institute (WCHRI).

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    Kasia Dzierlega & Toshifumi Yokota

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Dzierlega, K., Yokota, T. Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy. Gene Ther 27, 407–416 (2020). https://doi.org/10.1038/s41434-020-0156-6

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