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Gene augmentation prevents retinal degeneration in a CRISPR/Cas9-based mouse model of PRPF31 retinitis pigmentosa

Author

Listed:
  • Zhouhuan Xi

    (University of Pittsburgh
    Central South University
    University of Science and Technology of China)

  • Abhishek Vats

    (University of Pittsburgh)

  • José-Alain Sahel

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Yuanyuan Chen

    (University of Pittsburgh)

  • Leah C. Byrne

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

Abstract

Mutations in PRPF31 cause autosomal dominant retinitis pigmentosa, an untreatable form of blindness. Gene therapy is a promising treatment for PRPF31-retinitis pigmentosa, however, there are currently no suitable animal models in which to develop AAV-mediated gene augmentation. Here we establish Prpf31 mutant mouse models using AAV-mediated CRISPR/Cas9 knockout, and characterize the resulting retinal degeneration phenotype. Mouse models with early-onset morphological and functional impairments like those in patients were established, providing new platforms in which to investigate pathogenetic mechanisms and develop therapeutic methods. AAV-mediated PRPF31 gene augmentation restored the retinal structure and function in a rapidly degenerating mouse model, demonstrating the first in vivo proof-of-concept for AAV-mediated gene therapy to treat PRPF31-retinitis pigmentosa. AAV-CRISPR/Cas9-PRPF31 knockout constructs also mediated efficient PRPF31 knockout in human and non-human primate retinal explants, laying a foundation for establishing non-human primate models using the method developed here.

Suggested Citation

  • Zhouhuan Xi & Abhishek Vats & José-Alain Sahel & Yuanyuan Chen & Leah C. Byrne, 2022. "Gene augmentation prevents retinal degeneration in a CRISPR/Cas9-based mouse model of PRPF31 retinitis pigmentosa," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35361-8
    DOI: 10.1038/s41467-022-35361-8
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    Cited by:

    1. Milan Gautam & Antony Jozic & Grace Li-Na Su & Marco Herrera-Barrera & Allison Curtis & Sebastian Arrizabalaga & Wayne Tschetter & Renee C. Ryals & Gaurav Sahay, 2023. "Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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