title: Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD).
abstract: 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 aDUX4gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stableDUX4mRNAs. In addition, an open chromatin structure is required forDUX4gene 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 ofDUX4mRNAs observed in muscle and stem cells; and the use of antisense oligonucleotides (AOs) targeting theDUX4mRNA 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.
authors.affiliation: Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Avenue du Champ de Mars 6, 7000-Mons, Belgium. eugenie.ansseau@umons.ac.be.
authors.forename: Eugénie
authors.initials: E
authors.lastname: Ansseau
authors.affiliation: Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Avenue du Champ de Mars 6, 7000-Mons, Belgium. Celine.Vanderplanck@sgs.com.
authors.forename: Céline
authors.initials: C
authors.lastname: Vanderplanck
authors.affiliation: Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Avenue du Champ de Mars 6, 7000-Mons, Belgium. armelle.wauters@umons.ac.be.
authors.forename: Armelle
authors.initials: A
authors.lastname: Wauters
authors.affiliation: Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA. scott.harper@nationwidechildrens.org.|Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. scott.harper@nationwidechildrens.org.
authors.forename: Scott Q
authors.initials: SQ
authors.lastname: Harper
authors.affiliation: Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Avenue du Champ de Mars 6, 7000-Mons, Belgium. frederique.coppee@umons.ac.be.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Coppée
authors.affiliation: Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Avenue du Champ de Mars 6, 7000-Mons, Belgium. alexandra.belayew@umons.ac.be.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Belayew
keywords: double homeobox; myopathy; polyadenylation; primary myoblasts; splicing interference