In vivo base editing rescues photoreceptors in a mouse model of retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) is a group of retinal diseases that cause the progressive death of retinal photoreceptor cells and eventually blindness. Mutations in the {beta}-domain of the phosphodiesterase 6 (Pde6b) gene are among the most identified causes of autosomal recessive RP. Here, we report a base editing approach in which adeno-associated virus (AAV)-mediated adenine base editor (ABE) delivery to postmitotic photoreceptors is used to correct the Pde6b mutation in a retinal degeneration 10 (rd10) mouse model of RP. Subretinal delivery of AAV8-ABE corrects Pde6b mutation with up to 37.41% efficiency at the DNA level and up to 91.95% efficiency at the cDNA level, restores PDE6B expression, preserves photoreceptors and rescues visual function. RNA-seq reveals upregulation of genes associated with phototransduction and photoreceptor survival. Our data demonstrate that base editing is a potential gene therapy that could provide durable protection against RP.