@article{b6d53a6b2d10406eba6c89d948ca2ce9,
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.",
author = "Chen, {Jennifer C.J.} and King, {Oliver D.} and Yuanfan Zhang and Clayton, {Nicholas P.} and Carrie Spencer and Wentworth, {Bruce M.} and Emerson, {Charles P.} and Wagner, {Kathryn R.}",
note = "Funding Information: This work was supported by the NIH (R21NS079529 to K.R.W. and U54HD060848 to C.P.E.). All authors contributed to the study design. N.P.C. and B.M.W. provided reagents. J.C.J.C., Y.Z., C.S., and N.P.C. conducted experiments. J.C.J.C., O.D.K., Y.Z., N.P.C., C.P.E., and K.R.W. analyzed data. J.C.J.C., Y.Z., O.D.K., C.P.E., and K.R.W. wrote the manuscript. The authors acknowledge Takako I. Jones and Peter L. Jones for DUX4 detection methodology; Genila Bibat, Daniel Perez and the FSH Society, Inc. for assistance with patient recruitment and biopsy procurement; and Steven A. Moore and the University of Iowa Diagnostic Lab for genotyping of FSHD subjects. N.P.C. is an employee/shareholder of Sanofi Genzyme. B.M.W. is an employee/shareholder of Sarepta and of Sanofi Genzyme. Other authors have declared no conflicts of interest. Publisher Copyright: {\textcopyright} The American Society of Gene and Cell Therapy.",
year = "2016",
month = aug,
day = "1",
doi = "10.1038/mt.2016.111",
language = "English (US)",
volume = "24",
pages = "1405--1411",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "8",
}