Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics.

Mark McIntosh,'s picture
PubMed URL: 
http://www.ncbi.nlm.nih.gov/pubmed/27378237
Author: 
Wagner KR
Author List: 
Chen JC
King OD
Zhang Y
Clayton NP
Spencer C
Wentworth BM
Emerson CP Jr
Wagner KR
Journal: 
Mol Ther
PubMed ID: 
27378237
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.Molecular Therapy (2016); doi:10.1038/mt.2016.111.
Published Date: 
July, 2016

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