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

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.