Adenine base editing-mediated exon skipping restores dystrophin in humanized Duchenne mouse model

Jiajia Lin, Ming Jin, Dong Yang, Zhifang Li, Yu Zhang, Qingquan Xiao, Yin Wang, Yuyang Yu, Xiumei Zhang, Zhurui Shao, Linyu Shi, Shu Zhang, Wan-jin Chen, Ning Wang (), Shiwen Wu (), Hui Yang (), Chunlong Xu () and Guoling Li ()
Additional contact information
Jiajia Lin: Fujian Medical University
Ming Jin: Fujian Medical University
Dong Yang: HuidaGene Therapeutics Inc.
Zhifang Li: Lingang Laboratory
Yu Zhang: HuidaGene Therapeutics Inc.
Qingquan Xiao: HuidaGene Therapeutics Inc.
Yin Wang: HuidaGene Therapeutics Inc.
Yuyang Yu: HuidaGene Therapeutics Inc.
Xiumei Zhang: HuidaGene Therapeutics Inc.
Zhurui Shao: HuidaGene Therapeutics Inc.
Linyu Shi: HuidaGene Therapeutics Inc.
Shu Zhang: First Medical Center of Chinese PLA General Hospital
Wan-jin Chen: Fujian Medical University
Ning Wang: Fujian Medical University
Shiwen Wu: First Medical Center of Chinese PLA General Hospital
Hui Yang: HuidaGene Therapeutics Inc.
Chunlong Xu: Lingang Laboratory
Guoling Li: Fujian Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Duchenne muscular dystrophy (DMD) affecting 1 in 3500–5000 live male newborns is the frequently fatal genetic disease resulted from various mutations in DMD gene encoding dystrophin protein. About 70% of DMD-causing mutations are exon deletion leading to frameshift of open reading frame and dystrophin deficiency. To facilitate translating human DMD-targeting CRISPR therapeutics into patients, we herein establish a genetically humanized mouse model of DMD by replacing exon 50 and 51 of mouse Dmd gene with human exon 50 sequence. This humanized mouse model recapitulats patient’s DMD phenotypes of dystrophin deficiency and muscle dysfunction. Furthermore, we target splicing sites in human exon 50 with adenine base editor to induce exon skipping and robustly restored dystrophin expression in heart, tibialis anterior and diaphragm muscles. Importantly, systemic delivery of base editor via adeno-associated virus in the humanized male mouse model improves the muscle function of DMD mice to the similar level of wildtype ones, indicating the therapeutic efficacy of base editing strategy in treating most of DMD types with exon deletion or point mutations via exon-skipping induction.

Date: 2024
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DOI: 10.1038/s41467-024-50340-x

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