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Review
. 2017 Oct;27(5):251-259.
doi: 10.1089/nat.2017.0682. Epub 2017 Aug 10.

Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues

Annemieke Aartsma-Rus  1   2 , Volker Straub  2 , Robert Hemmings  3 , Manuel Haas  4 , Gabriele Schlosser-Weber  5 , Violeta Stoyanova-Beninska  6 , Eugenio Mercuri  7   8 , Francesco Muntoni  9 , Bruno Sepodes  10 , Elizabeth Vroom  11 , Pavel Balabanov  4
Affiliations
Review

Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues

Annemieke Aartsma-Rus et al. Nucleic Acid Ther. 2017 Oct.

Abstract

Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience.

Keywords: exon skipping; oligonucleotides; regulatory approval.

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Conflict of interest statement

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the agencies or organizations with which the authors are affiliated. A.A.R. discloses being employed by LUMC, which has patents on exon-skipping technology. As coinventor of some of these patents A.A.R. is entitled to a share of royalties. A.A.R. further discloses being ad hoc consultant for PTC Therapeutics, BioMarin Pharmaceuticals, Inc., Guidepoint Global and GLG consultancy, Grunenthal, Wave Therapeutics and BioClinica, having been a member of the Duchenne Network Steering Committee (BioMarin Pharmaceuticals, Inc.) and being a member of the scientific advisory boards of ProQR and Philae Pharmaceuticals. Remuneration for these activities is paid to LUMC. LUMC also received speaker honoraria from PTC Therapeutics and BioMarin Pharmaceuticals, Inc. V.S. is or has been a principal investigator for trials sponsored by Biogen, GSK, Ionis Pharmaceuticals, Prosensa/BioMarin Pharmaceuticals, Inc., Sanofi Genzyme and Sarepta Therapeutics. He has received speaker honoraria from Sanofi Genzyme and is or has over the last 3 years been on advisory boards for Audentes Therapeutics, Biogen, BioMarin Pharmaceuticals, Inc., Bristol-Myer Squibb, Italfarmaco SpA, Sarepta Therapeutics, Summit Therapeutics, Tivorsan, TrophyNOD, and Wave Therapeutics. He has research collaborations with Ultragenyx and Sanofi Genzyme. F.M. is supported by the National Institute of Health Research Biomedical Research Center at Great Ormond Street Hospital for Children NHS Foundation Trust. He is or has been a principal investigator for trials sponsored by Biogen; GSK; Ionis Pharmaceuticals; Prosensa/BioMarin Pharmaceuticals, Inc.; Pfizer; PTC Therapeutics; Roche; Sarepta Therapeutics; Audentes; EspeRare; Summit Therapeutics; and Genethon. Over the last 3 years he has been on advisory boards for Pfizer; Akashi Therapeutics, Biogen; Catabasis, Italfarmaco, Roche, Sarepta Therapeutics, Tivorsan, Wave Therapeutics, and Avexis. All other authors declare no conflicts of interest.

Figures

<b>FIG. 1.</b>
FIG. 1.
Schematic depiction of the reading frame rule and the exon-skipping approach. Top panel: a deletion of exon 45 disrupts the reading frame (exon 44 and 46 do not “fit”) and is associated with DMD, whereas a deletion of exon 44 and 45 maintains the reading frame (exon 43 and 46 would “fit”) and is associated with BMD. Using AONs, the pre-mRNA splicing process can be manipulated. In this example AONs targeting exon 44 hide this exon from the splicing machinery, causing exon 43 to be joined to exon 46, which restores the reading frame and allows production of a BMD-like dystrophin. Bottom panel: antisense-mediated exon skipping is a mutation-specific approach. For example, a deletion of exon 48–50 requires the skipping of exon 51 to restore the reading frame and allow the production of a BMD-like dystrophy. AONs, antisense oligonucleotide; BMD, Becker muscular dystrophy; DMD, Duchenne muscular dystrophy; mRNA, messenger RNA.
See this image and copyright information in PMC

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