Functional improvement of dystrophic muscle by utrophin gene editing
- 1Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- 2Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
- 3Division of Infectious Diseases and Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Abstract
Utrophin upregulation is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). Utrophin expression is post-transcriptionally repressed via microRNAs binding the 3' UTR of utrophin, particularly at the inhibitory microRNA target region (IMTR). Guide RNA pairs for editing the IMTR and a larger IMTR⁺ region were designed and ranked by their ability to edit and increase utrophin expression in normal and dystrophic muscle cells in vitro. Optimized guide RNA pairs and SpCas9 were used to generate MyoAAV vectors and tested for the ability to ameliorate the dystrophic phenotype of the mdx mouse model of DMD, in vivo. Systemic delivery of MyoAAV targeting the IMTR and IMTR⁺ using intraperitoneal injections in neonatal mdx mice resulted in efficient gene editing and increased utrophin expression in muscle. Increased utrophin was appropriately localized and accompanied by the appearance α-sarcoglycan at the sarcolemma, indicating dystrophin-associated glycoprotein complex recovery. Functional analyses revealed increased specific force generation and improved resistance to eccentric contractions. Histological analyses showed a reduction in the proportion of centrally nucleated fibers that are indicative of dystrophic pathology in the mdx mice. Together, this provides proof-of-concept for a novel therapeutic strategy that, in principle, would be applicable to all patients with DMD, independent of mutation status.
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BibTeX
@article{ghosh2026functional,
title = {{Functional improvement of dystrophic muscle by utrophin gene editing}},
author = {Trinath Ghosh and SK Tousif Ahamed and Junchao Xu and Xuexiang Han and Istvan Tombacz and Lesley S. Chaboub and Michael J. Mitchell and Drew Weissman and Tejvir S. Khurana},
journal = {Molecular therapy. Advances},
year = {2026},
month = oct,
doi = {10.1016/j.omta.2026.201857},
url = {https://europepmc.org/article/PMC/PMC13718585},
note = {CC BY},
}
RIS
TY - JOUR
TI - Functional improvement of dystrophic muscle by utrophin gene editing
AU - Trinath Ghosh
AU - SK Tousif Ahamed
AU - Junchao Xu
AU - Xuexiang Han
AU - Istvan Tombacz
AU - Lesley S. Chaboub
AU - Michael J. Mitchell
AU - Drew Weissman
AU - Tejvir S. Khurana
PY - 2026
DA - 2026/10/01
JO - Molecular therapy. Advances
DO - 10.1016/j.omta.2026.201857
UR - https://europepmc.org/article/PMC/PMC13718585
AB - Utrophin upregulation is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). Utrophin expression is post-transcriptionally repressed via microRNAs binding the 3' UTR of utrophin, particularly at the inhibitory microRNA target region (IMTR). Guide RNA pairs for editing the IMTR and a larger IMTR⁺ region were designed and ranked by their ability to edit and increase utrophin expression in normal and dystrophic muscle cells in vitro. Optimized guide RNA pairs and SpCas9 were used to generate MyoAAV vectors and tested for the ability to ameliorate the dystrophic phenotype of the mdx mouse model of DMD, in vivo. Systemic delivery of MyoAAV targeting the IMTR and IMTR⁺ using intraperitoneal injections in neonatal mdx mice resulted in efficient gene editing and increased utrophin expression in muscle. Increased utrophin was appropriately localized and accompanied by the appearance α-sarcoglycan at the sarcolemma, indicating dystrophin-associated glycoprotein complex recovery. Functional analyses revealed increased specific force generation and improved resistance to eccentric contractions. Histological analyses showed a reduction in the proportion of centrally nucleated fibers that are indicative of dystrophic pathology in the mdx mice. Together, this provides proof-of-concept for a novel therapeutic strategy that, in principle, would be applicable to all patients with DMD, independent of mutation status.
SN - 3117-387X
ER -