Activation of endogenous full-length utrophin by MyoAAV-UA as a therapeutic approach for Duchenne muscular dystrophy

Ruo Wu, Peng Li, Puhao Xiao, Shu Zhang, Xiaopeng Wang, Jie Liu, Wenjie Sun, Yue Chang, Xiuyi Ai, Lijiao Chen, Yan Zhuo, Jiaojian Wang, Zhengbo Wang, Shangang Li, Yuanyuan Li, Weizhi Ji (), Wenting Guo (), Shiwen Wu () and Yongchang Chen ()
Additional contact information
Ruo Wu: Kunming University of Science and Technology
Peng Li: Kunming University of Science and Technology
Puhao Xiao: Kunming University of Science and Technology
Shu Zhang: First Medical Center of Chinese PLA General Hospital
Xiaopeng Wang: Kunming University of Science and Technology
Jie Liu: Kunming University of Science and Technology
Wenjie Sun: Kunming University of Science and Technology
Yue Chang: First Medical Center of Chinese PLA General Hospital
Xiuyi Ai: First Medical Center of Chinese PLA General Hospital
Lijiao Chen: Kunming University of Science and Technology
Yan Zhuo: Kunming University of Science and Technology
Jiaojian Wang: Kunming University of Science and Technology
Zhengbo Wang: Kunming University of Science and Technology
Shangang Li: Kunming University of Science and Technology
Yuanyuan Li: Kunming University of Science and Technology
Weizhi Ji: Kunming University of Science and Technology
Wenting Guo: Kunming University of Science and Technology
Shiwen Wu: First Medical Center of Chinese PLA General Hospital
Yongchang Chen: Kunming University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Activation of endogenous full-length utrophin, a dystrophin homolog, presents an attractive therapeutic strategy for Duchenne muscular dystrophy (DMD), regardless of mutation types and loci. However, current dCas9-based activators are too large for efficient adeno-associated virus delivery, and the feasibility and durability of such treatments remain unclear. Here, we develop a muscle-targeted utrophin activation system using the compact dCasMINI-VPR system, termed MyoAAV-UA. Systemic administration of MyoAAV-UA in male mdx mice leads to substantial upregulation of utrophin at the sarcolemma, resulting in significant improvements in skeletal muscle function and a slowing of heart function deterioration. These benefits remain observable at six months post-treatment. In male nonhuman primates, systemic administration of MyoAAV-UA increases utrophin expression by twofold in skeletal muscle, with no significant side effects observed. Furthermore, MyoAAV-UA upregulates utrophin and utrophin-glycoprotein complexes in induced pluripotent stem cell-derived myotubes from DMD patients. In conclusion, these findings demonstrate the potential of MyoAAV-UA as a therapeutic approach for DMD.

Date: 2025
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DOI: 10.1038/s41467-025-57831-5

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