DUX4 reduction and muscle function improvement by subcutaneous delivery of gapmer antisense oligonucleotides

Authors

• Aiping Zhang, Center for Precision Medicine and Genomic Research, Children's National Hospital, Washington, DC 20010, USA.
• Kenji Rowel Lim, Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2H7, Canada.
• Ze Chen, Center for Precision Medicine and Genomic Research, Children's National Hospital, Washington, DC 20010, USA.
• Toshifumi Yokota, Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2H7, Canada.
• Yi-Wen Chen, Center for Precision Medicine and Genomic Research, Children's National Hospital, Washington, DC 20010, USA.

Document Type

Journal Article

Publication Date

3-12-2026

Journal

Molecular therapy. Nucleic acids

Volume

37

Issue

1

DOI

10.1016/j.omtn.2025.102791

Keywords

D4Z4; DUX4; FSHD; MT: Oligonucleotides: therapies and applications; antisense oligonucleotide; gapmer

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is caused by aberrant expression of double homeodomain protein 4 (DUX4). The disease has no effective treatment. Previously we demonstrated effective DUX4 knockdown in vitro and in vivo using 2'-O-methoxyethyl (2'MOE) and locked nucleic acid (LNA) gapmer antisense oligonucleotides delivered via intramuscular injections. This study aimed to evaluate in vivo efficacy of the gapmers via systemic delivery using mouse models expressing DUX4 at different levels. First, we injected the gapmers subcutaneously to FLExDUX4 mice at 20 mg/kg twice a week for 10 weeks. Results showed significant reduction in DUX4 mRNA and improved muscle function, assessed by grip strength. Muscle fibrosis and circulating TGFβ1 levels were significantly reduced, approaching baseline level. A dose-dependent DUX4 reduction was observed in 2'MOE gapmer treated. In the ACTA1-MCM;FLExDUX4 model, where DUX4 expression was induced by tamoxifen (5 mg/kg), treatment with 2'MOE gapmers effectively reduced DUX4, improved muscle function, and decreased inflammation. These findings highlight the therapeutic potential of gapmer-based DUX4 reduction, leading to phenotypic improvement and restoration of muscle function in FSHD mouse models.

APA Citation

Zhang, Aiping; Lim, Kenji Rowel; Chen, Ze; Yokota, Toshifumi; and Chen, Yi-Wen, "DUX4 reduction and muscle function improvement by subcutaneous delivery of gapmer antisense oligonucleotides" (2026). GW Authored Works. Paper 8891.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8891

Department

Pediatrics