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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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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10525656/
https://www.ncbi.nlm.nih.gov/pubmed/37760780
http://dx.doi.org/10.3390/biomedicines11092339
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author 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
author_facet 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
author_sort Kakimoto, Tetsuhiro
collection PubMed
description 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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spelling pubmed-105256562023-09-28 A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice 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 Biomedicines Article 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. MDPI 2023-08-22 /pmc/articles/PMC10525656/ /pubmed/37760780 http://dx.doi.org/10.3390/biomedicines11092339 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice
title A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice
title_full A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice
title_fullStr A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice
title_full_unstemmed A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice
title_short A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice
title_sort systemically administered unconjugated antisense oligonucleotide targeting dux4 improves muscular injury and motor function in fshd model mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10525656/
https://www.ncbi.nlm.nih.gov/pubmed/37760780
http://dx.doi.org/10.3390/biomedicines11092339
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