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

Author

Listed:
  • 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.
    Shanghai Center for Brain Science and Brain-Inspired Technology)

  • Chunlong Xu

    (Lingang Laboratory
    Shanghai Center for Brain Science and Brain-Inspired Technology)

  • Guoling Li

    (Fujian Medical University
    HuidaGene Therapeutics Inc.)

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.

Suggested Citation

  • 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 , 2024. "Adenine base editing-mediated exon skipping restores dystrophin in humanized Duchenne mouse model," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50340-x
    DOI: 10.1038/s41467-024-50340-x
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    References listed on IDEAS

    as
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