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, X. Ai, Lijiao Chen, Yan Zhuo, Jiaojian Wang, Zhengbo Wang, Shangang Li, Yuanyuan Li, Weizhi Ji, Wenting Guo, Shiwen Wu, Yongchang Chen
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. Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by mutations in the DMD gene. Here, the authors develop MyoAAV-UA, a compact utrophin activator, as a promising universal treatment for DMD through a homologous protein activation approach.