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

Retinitis pigmentosa (RP) is a group of retinal diseases that cause the progressive death of retinal photoreceptor cells and eventu-ally blindness. Mutations in the b-domain of the phosphodies-terase 6 (Pde6b) gene are the most identified causes of autosomal recessive RP. Clinically, there is no effective treatment so far that can stop the progression of RP and restore the vision. Here, we report a base editing approach in which adeno-associated virus (AAV)-mediated adenine base editor (ABE) delivering to post-mitotic photoreceptors was conducted to correct the Pde6b mu-tation in a retinal degeneration 10 (rd10) mouse model of RP. Subretinal delivery of AAV8-ABE corrected Pde6b mutation with averaging up to 20.79% efficiency at the DNA level and 54.97% efficiency at the cDNA level without bystanders, restored PDE6B expression, preserved photoreceptors, and rescued visual function. RNA-seq revealed the preservation of genes associated with phototransduction and photoreceptor survival. Our data have demonstrated that base editing is a potential gene therapy that could provide durable protection against RP.

Automated summary

Retinitis pigmentosa (RP) is a group of retinal diseases that cause progressive retinal photoreceptor cell death and ultimately blindness. A base editing approach using adeno-associated virus (AAV)-mediated adenine base editor (ABE) was used to correct the Pde6bmutation in a mouse model of RP, resulting in restored PDE6B expression, preserved photoreceptors, and rescued visual function with high efficiency.