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Efficient precise in vivo base editing in adult dystrophic mice

Author

Listed:
  • Li Xu

    (The Ohio State University Wexner Medical Center)

  • Chen Zhang

    (The Ohio State University Wexner Medical Center)

  • Haiwen Li

    (The Ohio State University Wexner Medical Center)

  • Peipei Wang

    (The Ohio State University Wexner Medical Center)

  • Yandi Gao

    (The Ohio State University Wexner Medical Center)

  • Nahush A. Mokadam

    (The Ohio State University Wexner Medical Center)

  • Jianjie Ma

    (The Ohio State University Wexner Medical Center)

  • W. David Arnold

    (The Ohio State University Wexner Medical Center)

  • Renzhi Han

    (The Ohio State University Wexner Medical Center)

Abstract

Recent advances in base editing have created an exciting opportunity to precisely correct disease-causing mutations. However, the large size of base editors and their inherited off-target activities pose challenges for in vivo base editing. Moreover, the requirement of a protospacer adjacent motif (PAM) nearby the mutation site further limits the targeting feasibility. Here we modify the NG-targeting adenine base editor (iABE-NGA) to overcome these challenges and demonstrate the high efficiency to precisely edit a Duchenne muscular dystrophy (DMD) mutation in adult mice. Systemic delivery of AAV9-iABE-NGA results in dystrophin restoration and functional improvement. At 10 months after AAV9-iABE-NGA treatment, a near complete rescue of dystrophin is measured in mdx4cv mouse hearts with up to 15% rescue in skeletal muscle fibers. The off-target activities remains low and no obvious toxicity is detected. This study highlights the promise of permanent base editing using iABE-NGA for the treatment of monogenic diseases.

Suggested Citation

  • Li Xu & Chen Zhang & Haiwen Li & Peipei Wang & Yandi Gao & Nahush A. Mokadam & Jianjie Ma & W. David Arnold & Renzhi Han, 2021. "Efficient precise in vivo base editing in adult dystrophic mice," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23996-y
    DOI: 10.1038/s41467-021-23996-y
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    Cited by:

    1. 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.
    2. Yuan Zhou & Chen Zhang & Weidong Xiao & Roland W. Herzog & Renzhi Han, 2024. "Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Haiwen Li & Peipei Wang & Chen Zhang & Yuanbojiao Zuo & Yuan Zhou & Renzhi Han, 2023. "Defective BVES-mediated feedback control of cAMP in muscular dystrophy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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