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A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor
Tetsuhiro Kakimoto1, Akira Ogasawara1, Kiyoshi Ishikawa1
1Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan.
Biomedicines
|September 28, 2023
Summary
A novel antisense oligonucleotide (ASO), MT-DUX4-ASO, effectively reduced DUX4 gene expression and improved muscle function in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). Systemic administration of this ASO shows promise for treating FSHD without targeted delivery.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Facioscapulohumeral muscular dystrophy (FSHD) is a common genetic disorder characterized by progressive muscle weakness due to abnormal DUX4 gene expression.
- Current therapeutic strategies for FSHD are limited, highlighting the need for novel treatment approaches.
Purpose of the Study:
- To investigate the efficacy of MT-DUX4-ASO, a novel gapmer antisense oligonucleotide (ASO), in treating facioscapulohumeral muscular dystrophy (FSHD).
- To evaluate the potential of systemically administered ASOs as a therapeutic strategy for FSHD.
Main Methods:
- MT-DUX4-ASO was tested in vitro using FSHD patient-derived myoblasts and in vivo using the ACTA1-MCM/FLExDUX4 (DUX4-TG) mouse model of FSHD.
- DUX4 gene expression, target gene activity, muscle injury markers, and motor function (treadmill test, muscle force) were assessed.
Main Results:
- MT-DUX4-ASO significantly decreased DUX4 and its target gene expression in patient-derived myoblasts.
- Systemic administration of MT-DUX4-ASO suppressed DUX4 target gene expression, histological muscle injury, and elevated muscle injury markers in DUX4-TG mice.
- MT-DUX4-ASO treatment prevented declines in running speed and muscle force in DUX4-TG mice, demonstrating improved motor function.
Conclusions:
- Systemically administered, unconjugated MT-DUX4-ASO effectively suppressed DUX4-driven disease progression in a mouse model of FSHD.
- This study establishes the potential of unconjugated antisense oligonucleotides as a promising therapeutic strategy for facioscapulohumeral muscular dystrophy.
