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Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies

Published online by Cambridge University Press:  02 October 2019

Jaeho Hwang  and
Toshifumi Yokota Open the ORCID record for Toshifumi Yokota [Opens in a new window]
Jaeho Hwang
Affiliation:
Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton Canada
Toshifumi Yokota*
Affiliation:
Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton Canada Muscular Dystrophy Canada Research Chair, Edmonton Canada
*
Author for correspondence: Toshifumi Yokota, E-mail: toshifumi.yokota@ualberta.ca
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Abstract

Muscular dystrophy is a group of genetic disorders characterised by degeneration of muscles. Different forms of muscular dystrophy can show varying phenotypes with a wide range of age, severity and location of muscle deterioration. Many palliative care options are available for muscular dystrophy patients, but no curative treatment is available. Exon-skipping therapy aims to induce skipping of exons with disease-causing mutations and/or nearby exons to restore the reading frame, which results in an internally truncated, partially functional protein. In antisense-mediated exon-skipping synthetic antisense oligonucleotide binds to pre-mRNA to induce exon skipping. Recent advances in exon skipping have yielded promising results; the US Food and Drug Administration (FDA) approved eteplirsen (Exondys51) as the first exon-skipping drug for the treatment of Duchenne muscular dystrophy, and in vivo exon skipping has been demonstrated in animal models of dysferlinopathy, limb-girdle muscular dystrophy type 2C and congenital muscular dystrophy type 1A. Novel methods that induce exon skipping utilizing Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are also being developed where splice site mutations are created within the genome to induce exon skipping. Challenges remain as exon-skipping agents can have deleterious non-specific effects and different in-frame deletions show phenotypic variance. This article reviews the state of the art of exon skipping for treating muscular dystrophy and discusses challenges and future prospects.

Keywords

Antisense oligonucleotideCRISPRDuchenne muscular dystrophydysferlinopathyeteplirsenexon skippinggenome editingGolodirsenlimb-girdle muscular dystrophy type 2CNS-065/NCNP-01 (viltolarsen)splice modulation
Type
Invited Review
Information
Expert Reviews in Molecular Medicine , Volume 21 , 2019 , e5
Copyright
Copyright © Cambridge University Press 2019 

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