Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics

Jennifer CJ Chen, Oliver D. King, Yuanfan Zhang, Nicholas P. Clayton, Carrie Spencer, Bruce M. Wentworth, Charles P. Emerson, Kathryn Rae Wagner

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StateAccepted/In press - Jul 5 2016

Fingerprint

Facioscapulohumeral Muscular Dystrophy
Morpholinos
Skeletal Muscle Fibers
Heterografts
Therapeutics
Polyadenylation
Electroporation
Skeletal Muscle
RNA
Pathology
Muscles

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. / Chen, Jennifer CJ; King, Oliver D.; Zhang, Yuanfan; Clayton, Nicholas P.; Spencer, Carrie; Wentworth, Bruce M.; Emerson, Charles P.; Wagner, Kathryn Rae.

In: Molecular Therapy, 05.07.2016.

Research output: Contribution to journalArticle

Chen, Jennifer CJ ; King, Oliver D. ; Zhang, Yuanfan ; Clayton, Nicholas P. ; Spencer, Carrie ; Wentworth, Bruce M. ; Emerson, Charles P. ; Wagner, Kathryn Rae. / Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. In: Molecular Therapy. 2016.
@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.Molecular Therapy (2016); doi:10.1038/mt.2016.111.",
author = "Chen, {Jennifer CJ} 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 Rae}",
year = "2016",
month = "7",
day = "5",
doi = "10.1038/mt.2016.111",
language = "English (US)",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics

AU - Chen, Jennifer CJ

AU - King, Oliver D.

AU - Zhang, Yuanfan

AU - Clayton, Nicholas P.

AU - Spencer, Carrie

AU - Wentworth, Bruce M.

AU - Emerson, Charles P.

AU - Wagner, Kathryn Rae

PY - 2016/7/5

Y1 - 2016/7/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84977117458&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84977117458&partnerID=8YFLogxK

U2 - 10.1038/mt.2016.111

DO - 10.1038/mt.2016.111

M3 - Article

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

ER -