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Genes 2017, 8(3), 93;

Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD)

Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Avenue du Champ de Mars 6, 7000-Mons, Belgium
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA
Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Present address: SGS Biopharma, Vieux Chemin du Poète 10, 1301 Wavre, Belgium
Author to whom correspondence should be addressed.
Academic Editors: Susan Fletcher and Steve Wilton
Received: 26 December 2016 / Revised: 16 February 2017 / Accepted: 22 February 2017 / Published: 3 March 2017
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a DUX4 gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable DUX4 mRNAs. In addition, an open chromatin structure is required for DUX4 gene transcription. FSHD thus results from a gain of function of the toxic DUX4 protein that normally is only expressed in germ line and stem cells. Therapeutic strategies are emerging that aim to decrease DUX4 expression or toxicity in FSHD muscle cells. We review here the heterogeneity of DUX4 mRNAs observed in muscle and stem cells; and the use of antisense oligonucleotides (AOs) targeting the DUX4 mRNA to interfere either with transcript cleavage/polyadenylation or intron splicing. We show in primary cultures that DUX4-targeted AOs suppress the atrophic FSHD myotube phenotype; but do not improve the disorganized FSHD myotube phenotype which could be caused by DUX4c over-expression. Thus; DUX4c might constitute another therapeutic target in FSHD. View Full-Text
Keywords: double homeobox; splicing interference; polyadenylation; primary myoblasts; myopathy double homeobox; splicing interference; polyadenylation; primary myoblasts; myopathy

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Ansseau, E.; Vanderplanck, C.; Wauters, A.; Harper, S.Q.; Coppée, F.; Belayew, A. Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD). Genes 2017, 8, 93.

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