A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice

A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice

Facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscular dystrophies, is caused by an abnormal expression of the DUX4 gene in skeletal muscles, resulting in muscle weakness. In this study, we investigated MT-DUX4-ASO, a novel gapmer antisense oligonucleotide (ASO). MT-DUX4-ASO...

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Bibliographic Details
Published in:Biomedicines Vol. 11; no. 9; p. 2339
Main Authors: Kakimoto, Tetsuhiro, Ogasawara, Akira, Ishikawa, Kiyoshi, Kurita, Takashi, Yoshida, Kumiko, Harada, Shuichi, Nonaka, Taeko, Inoue, Yoshimi, Uchida, Keiko, Tateoka, Takashi, Ohta, Tetsuya, Kumagai, Shinji, Sasaki, Takashi, Aihara, Hajime
Format: Journal Article
Language:English
Published: Basel MDPI AG 22-08-2023
MDPI
Subjects:
Analysis
Animal models
Antibodies
antisense oligonucleotide
Antisense oligonucleotides
Antisense therapy
Drug delivery
Drug delivery systems
Drugs
DUX4
Epigenetics
facioscapulohumeral muscular dystrophy
Fitness equipment
Gene expression
Genes
Ligands
motor function
muscle force
muscle injury
Muscles
Muscular dystrophy
Myoblasts
Patients
Penicillin
Regression analysis
Running
Scientific equipment and supplies industry
Skeletal muscle
Vehicles
United States
Japan
United States > US
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Summary:Facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscular dystrophies, is caused by an abnormal expression of the DUX4 gene in skeletal muscles, resulting in muscle weakness. In this study, we investigated MT-DUX4-ASO, a novel gapmer antisense oligonucleotide (ASO). MT-DUX4-ASO decreased the expression of DUX4 and its target genes in FSHD patient-derived myoblasts. For the first time, we demonstrated that a systemically administered ASO, even without a ligand for drug delivery, could significantly improve muscle injury and motor function in the ACTA1-MCM/FLExDUX4 (DUX4-TG) mouse model of FSHD. Tamoxifen (TMX) injection transiently induces skeletal-muscle-specific DUX4 expression in DUX4-TG mice, while the skeletal muscles of TMX-untreated DUX4-TG mice have leaky DUX4 expression in a small subset of myofibers similar to those of FSHD patients. Subcutaneous 10 mg/kg of MT-DUX4-ASO at two-week intervals significantly suppressed muscular DUX4 target gene expression, histological muscle injury, and blood muscle injury marker elevation in TMX-untreated DUX4-TG mice. Notably, MT-DUX4-ASO at 10 mg/kg every other week significantly prevented the TMX-induced declines in treadmill test running speed and muscle force in DUX4-TG mice. Thus, the systemically administered unconjugated MT-DUX4-ASO suppressed disease progression in DUX4-TG mice, extending the potential of unconjugated ASOs as a promising FSHD treatment strategy.
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These authors contributed equally to this work.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines11092339