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

Jing Su; Kaiqin She; Li Song; Xiu Jin; Ruiting Li; Qinyu Zhao; Jianlu Xiao; Danian Chen; Hui Cheng; Fang Lu; Yuquan Wei; Yang Yang

doi:10.1016/j.omtn.2023.02.011

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

Mol Ther Nucleic Acids. 2023 Feb 14:31:596-609. doi: 10.1016/j.omtn.2023.02.011. eCollection 2023 Mar 14.

Authors

Jing Su¹, Kaiqin She², Li Song¹, Xiu Jin¹, Ruiting Li¹, Qinyu Zhao¹, Jianlu Xiao¹, Danian Chen³, Hui Cheng⁴, Fang Lu², Yuquan Wei¹, Yang Yang^{2

1}

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China.
² Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
³ Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁴ Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

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 β-domain of the phosphodiesterase 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 postmitotic photoreceptors was conducted to correct the Pde6b mutation 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.

Keywords: MT: RNA/DNA editing; Pde6b; adeno-associated virus; base editing; photoreceptors degeneration; retinitis pigmentosa.