Nat Commun. 2023 Aug 15
Yidong Wu, Xiaoling Wan, Dongdong Zhao, Xuxu Chen, Yujie Wang, Xinxin Tang, Ju Li, Siwei Li, Xiaodong Sun, Changhao Bi, and Xueli Zhang
Products used in the paper Details Operation
AAV vector packaging AAV vectors were packaged and purified by PackGene Biotech, and the titers were 1 × 10^13 vg per ml. Request Quote

Research Field: eye; gene editing

Keywords: Targeted gene repair, Translational research, Retinal diseases

AAV Serotype: AAV5

Dose: One microliter of the compound containing AAV-N and AAV-C at a virus titer of 10^12 or balanced salt solution (BSS) was slowly and manually injected into the temporal subretinal space.

Routes of Administration: Subretinal injections were performed at P14 with an ophthalmic surgical microscope

Targeted organ: eye

Animal or cell line strain: Pigmented rd10 mice and C57BL/6 J mice

Abstract

Base editing technology is an ideal solution for treating pathogenic single-nucleotide variations (SNVs). No gene editing therapy has yet been approved for eye diseases, such as retinitis pigmentosa (RP). Here, we show, in the rd10 mouse model, which carries an SNV identified as an RP-causing mutation in human patients, that subretinal delivery of an optimized dual adeno-associated virus system containing the adenine base editor corrects the pathogenic SNV in the neuroretina with up to 49% efficiency. Light microscopy showed that a thick and robust outer nuclear layer (photoreceptors) was preserved in the treated area compared with the thin, degenerated outer nuclear layer without treatment. Substantial electroretinogram signals were detected in treated rd10 eyes, whereas control treated eyes showed minimal signals. The water maze experiment showed that the treatment substantially improved vision-guided behavior. Together, we construct and validate a translational therapeutic solution for the treatment of RP in humans. Our findings might accelerate the development of base-editing based gene therapies.

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