DUX4 Transcript Knockdown with Antisense 2'-O-Methoxyethyl Gapmers for the Treatment of Facioscapulohumeral Muscular Dystrophy.
2’-MOE gapmers
DUX4
FLExDUX4 mice
FSHD
antisense therapy
facioscapulohumeral muscular dystrophy
genetic disorder
immortalized FSHD patient-derived cell line
mRNA knockdown
skeletal muscle
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
03 02 2021
03 02 2021
Historique:
received:
01
06
2020
revised:
24
09
2020
accepted:
12
10
2020
pubmed:
18
10
2020
medline:
21
10
2021
entrez:
17
10
2020
Statut:
ppublish
Résumé
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by a progressive, asymmetric weakening of muscles, starting with those in the upper body. It is caused by aberrant expression of the double homeobox protein 4 gene (DUX4) in skeletal muscle. FSHD is currently incurable. We propose to develop a therapy for FSHD using antisense 2'-O-methoxyethyl (2'-MOE) gapmers, to knock down DUX4 mRNA expression. Using immortalized patient-derived muscle cells and local intramuscular injections in the FLExDUX4 FSHD mouse model, we showed that our designed 2'-MOE gapmers significantly reduced DUX4 transcript levels in vitro and in vivo, respectively. Furthermore, in vitro, we observed significantly reduced expression of DUX4-activated downstream targets, restoration of FSHD signature genes by RNA sequencing, significant improvements in myotube morphology, and minimal off-target activity. This work facilitates the development of a promising candidate therapy for FSHD and lays down the foundation for in vivo systemic treatment studies.
Identifiants
pubmed: 33068777
pii: S1525-0016(20)30544-X
doi: 10.1016/j.ymthe.2020.10.010
pmc: PMC7854280
pii:
doi:
Substances chimiques
Dux4 protein, mouse
0
Homeodomain Proteins
0
Oligonucleotides, Antisense
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
848-858Subventions
Organisme : NINDS NIH HHS
ID : R03 NS116444
Pays : United States
Organisme : CIHR
ID : 143251
Pays : Canada
Informations de copyright
Copyright © 2020 The American Society of Gene and Cell Therapy. All rights reserved.
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