Multiple Exon Skipping in the Duchenne Muscular Dystrophy Hot Spots: Prospects and Challenges
Laboratory of Biomedical Science, Department of Veterinary Medicine, Nihon University College of Bioresource Sciences, Fujisawa 252-0880, Japan
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2H7, Canada
Third Department of Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
Department of Neurology, National Hospital Organization, Matsumoto Medical Center, Matsumoto 399-8701, Japan
The Friends of Garrett Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Endowed Research Chair, Edmonton, AB, T6G2H7, Canada
Author to whom correspondence should be addressed.
J. Pers. Med. 2018, 8(4), 41; https://doi.org/10.3390/jpm8040041
Received: 31 October 2018 / Revised: 24 November 2018 / Accepted: 4 December 2018 / Published: 7 December 2018
(This article belongs to the Special Issue Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases)
Duchenne muscular dystrophy (DMD), a fatal X-linked recessive disorder, is caused mostly by frame-disrupting, out-of-frame deletions in the dystrophin (DMD) gene. Antisense oligonucleotide-mediated exon skipping is a promising therapy for DMD. Exon skipping aims to convert out-of-frame mRNA to in-frame mRNA and induce the production of internally-deleted dystrophin as seen in the less severe Becker muscular dystrophy. Currently, multiple exon skipping has gained special interest as a new therapeutic modality for this approach. Previous retrospective database studies represented a potential therapeutic application of multiple exon skipping. Since then, public DMD databases have become more useful with an increase in patient registration and advances in molecular diagnosis. Here, we provide an update on DMD genotype-phenotype associations using a global DMD database and further provide the rationale for multiple exon skipping development, particularly for exons 45–55 skipping and an emerging therapeutic concept, exons 3–9 skipping. Importantly, this review highlights the potential of multiple exon skipping for enabling the production of functionally-corrected dystrophin and for treating symptomatic patients not only with out-of-frame deletions but also those with in-frame deletions. We will also discuss prospects and challenges in multiple exon skipping therapy, referring to recent progress in antisense chemistry and design, as well as disease models.