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

Zhouhuan Xi, Abhishek Vats, José-Alain Sahel, Yuanyuan Chen and Leah C. Byrne ()
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Zhouhuan Xi: University of Pittsburgh
Abhishek Vats: University of Pittsburgh
José-Alain Sahel: University of Pittsburgh
Yuanyuan Chen: University of Pittsburgh
Leah C. Byrne: University of Pittsburgh

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35361-8

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