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In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa

Author

Listed:
  • Yidian Fu

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Xiaoyu He

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Liang Ma

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Xin D. Gao

    (Broad Institute of Harvard and MIT
    Harvard University
    Harvard University)

  • Pengpeng Liu

    (Southern University of Science and Technology)

  • Hanhan Shi

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Peiwei Chai

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Shengfang Ge

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Renbing Jia

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • David R. Liu

    (Broad Institute of Harvard and MIT
    Harvard University
    Harvard University)

  • Xianqun Fan

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Zhi Yang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

Abstract

The next-generation gene editing tool, prime editing (PE), is adept at correcting point mutations precisely with high editing efficiency and rare off-target events and shows promising therapeutic value in treating hereditary diseases. Retinitis pigmentosa (RP) is the most common type of inherited retinal dystrophy and is characterized by progressive degeneration of retinal photoreceptors and, consequently, visual decline. To date, effective treatments for RP are lacking. Herein, a PE system is designed to target the PDE6B Y347X mutation in the rd1 mouse strain, a preclinical RP model. We screen and develop the PE system with epegRNA and RTΔRnH, which is delivered via dual-AAV in vivo with an editing efficiency of 26.47 ± 13.35%, with negligible off-target effects confirmed by AID-Seq and PE-tag. Treatment with the PE system in vivo greatly restores PDE6B protein expression and protects rod cells from degeneration. Mouse behavioural experiments also show that compared with no treatment, prime editing inhibits vision deterioration in littermate rd1 mice. This study provides a therapeutic opportunity for the use of PE to correct mutated RPs at the genomic level.

Suggested Citation

  • Yidian Fu & Xiaoyu He & Liang Ma & Xin D. Gao & Pengpeng Liu & Hanhan Shi & Peiwei Chai & Shengfang Ge & Renbing Jia & David R. Liu & Xianqun Fan & Zhi Yang, 2025. "In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57628-6
    DOI: 10.1038/s41467-025-57628-6
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