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AAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa

Author

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  • Yidong Wu

    (Shanghai Jiao Tong University School of Medicine
    National Clinical Research Center for Eye Diseases
    Shanghai Key Laboratory of Ocular Fundus Diseases)

  • Xiaoling Wan

    (Shanghai Jiao Tong University School of Medicine
    National Clinical Research Center for Eye Diseases
    Shanghai Key Laboratory of Ocular Fundus Diseases)

  • Dongdong Zhao

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Xuxu Chen

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Yujie Wang

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Xinxin Tang

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Ju Li

    (Tianjin Normal University)

  • Siwei Li

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Xiaodong Sun

    (Shanghai Jiao Tong University School of Medicine
    National Clinical Research Center for Eye Diseases
    Shanghai Key Laboratory of Ocular Fundus Diseases)

  • Changhao Bi

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Xueli Zhang

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

Abstract

Base editing technology is an ideal solution for treating pathogenic single-nucleotide variations (SNVs). No gene editing therapy has yet been approved for eye diseases, such as retinitis pigmentosa (RP). Here, we show, in the rd10 mouse model, which carries an SNV identified as an RP-causing mutation in human patients, that subretinal delivery of an optimized dual adeno-associated virus system containing the adenine base editor corrects the pathogenic SNV in the neuroretina with up to 49% efficiency. Light microscopy showed that a thick and robust outer nuclear layer (photoreceptors) was preserved in the treated area compared with the thin, degenerated outer nuclear layer without treatment. Substantial electroretinogram signals were detected in treated rd10 eyes, whereas control treated eyes showed minimal signals. The water maze experiment showed that the treatment substantially improved vision-guided behavior. Together, we construct and validate a translational therapeutic solution for the treatment of RP in humans. Our findings might accelerate the development of base-editing based gene therapies.

Suggested Citation

  • Yidong Wu & Xiaoling Wan & Dongdong Zhao & Xuxu Chen & Yujie Wang & Xinxin Tang & Ju Li & Siwei Li & Xiaodong Sun & Changhao Bi & Xueli Zhang, 2023. "AAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40655-6
    DOI: 10.1038/s41467-023-40655-6
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    References listed on IDEAS

    as
    1. Alexis C. Komor & Yongjoo B. Kim & Michael S. Packer & John A. Zuris & David R. Liu, 2016. "Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage," Nature, Nature, vol. 533(7603), pages 420-424, May.
    2. Miguel M. Álvarez & Josep Biayna & Fran Supek, 2022. "TP53-dependent toxicity of CRISPR/Cas9 cuts is differential across genomic loci and can confound genetic screening," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Nicole M. Gaudelli & Alexis C. Komor & Holly A. Rees & Michael S. Packer & Ahmed H. Badran & David I. Bryson & David R. Liu, 2017. "Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage," Nature, Nature, vol. 551(7681), pages 464-471, November.
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