title: Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics.
abstract: Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here we report on the use of antisense phosphorodiamidate morpholino oligonucleotides to suppress DUX4 expression and function in FSHD myotubes and xenografts. The most effective was phosphorodiamidate morpholino oligonucleotide FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense phosphorodiamidate morpholino oligonucleotides as an FSHD therapeutic option.
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jennifer Cj
authors.initials: JC
authors.lastname: Chen
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Oliver D
authors.initials: OD
authors.lastname: King
authors.affiliation: The Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA.|Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Yuanfan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Sanofi Genzyme, Cambridge, Massachusetts, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clayton
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Spencer
authors.affiliation: Sanofi Genzyme, Cambridge, Massachusetts, USA.|Current address: Department of Biology, Sarepta Therapeutics, Cambridge, Massachusetts, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Wentworth
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Emerson
authors.affiliation: The Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA.|Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Wagner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D018390:Gene Targeting; D015316:Genetic Therapy; D064593:Heterografts; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D060172:Morpholinos / Q000008:administration & dosage / Q000235:genetics*; D018485:Muscle Fibers, Skeletal; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D059467:Transcriptome
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D060172:Morpholinos