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Biomedicines 2018, 6(1), 1; https://doi.org/10.3390/biomedicines6010001

Skipping Multiple Exons to Treat DMD—Promises and Challenges

1
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 8812-112 St. Edmonton, AB T6G 2H7, Canada
2
The Friends of Garrett Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair, 8812-112 St. Edmonton, AB T6G 2H7, Canada
*
Author to whom correspondence should be addressed.
Received: 29 November 2017 / Revised: 19 December 2017 / Accepted: 19 December 2017 / Published: 2 January 2018
(This article belongs to the Special Issue Antisense Therapy)
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Abstract

Duchenne muscular dystrophy (DMD) is a lethal disorder caused by mutations in the DMD gene. Antisense-mediated exon-skipping is a promising therapeutic strategy that makes use of synthetic nucleic acids to skip frame-disrupting exon(s) and allows for short but functional protein expression by restoring the reading frame. In 2016, the U.S. Food and Drug Administration (FDA) approved eteplirsen, which skips DMD exon 51 and is applicable to approximately 13% of DMD patients. Multiple exon skipping, which is theoretically applicable to 80–90% of DMD patients in total, have been demonstrated in animal models, including dystrophic mice and dogs, using cocktail antisense oligonucleotides (AOs). Although promising, current drug approval systems pose challenges for the use of a cocktail AO. For example, both exons 6 and 8 need to be skipped to restore the reading frame in dystrophic dogs. Therefore, the cocktail of AOs targeting these exons has a combined therapeutic effect and each AO does not have a therapeutic effect by itself. The current drug approval system is not designed to evaluate such circumstances, which are completely different from cocktail drug approaches in other fields. Significant changes are needed in the drug approval process to promote the cocktail AO approach. View Full-Text
Keywords: Duchenne/Becker muscular dystrophy (DMD/BMD); antisense oligonucleotides (AOs); multi-exon skipping; phosphorodiamidate morpholino oligomer (PMO; morpholino); eteplirsen; golodirsen; canine X-linked muscular dystrophy (CXMD); golden retriever muscular dystrophy (GRMD); Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated protein 9 (CRISPR/Cas9)-mediated genome editing; actin binding domain (ABD) Duchenne/Becker muscular dystrophy (DMD/BMD); antisense oligonucleotides (AOs); multi-exon skipping; phosphorodiamidate morpholino oligomer (PMO; morpholino); eteplirsen; golodirsen; canine X-linked muscular dystrophy (CXMD); golden retriever muscular dystrophy (GRMD); Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated protein 9 (CRISPR/Cas9)-mediated genome editing; actin binding domain (ABD)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Aslesh, T.; Maruyama, R.; Yokota, T. Skipping Multiple Exons to Treat DMD—Promises and Challenges. Biomedicines 2018, 6, 1.

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