AAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa

Yidong Wu, Xiaoling Wan (), Dongdong Zhao, Xuxu Chen, Yujie Wang, Xinxin Tang, Ju Li, Siwei Li, Xiaodong Sun (), Changhao Bi () and Xueli Zhang ()
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Yidong Wu: Shanghai Jiao Tong University School of Medicine
Xiaoling Wan: Shanghai Jiao Tong University School of Medicine
Dongdong Zhao: Chinese Academy of Sciences
Xuxu Chen: Chinese Academy of Sciences
Yujie Wang: Chinese Academy of Sciences
Xinxin Tang: Chinese Academy of Sciences
Ju Li: Tianjin Normal University
Siwei Li: Chinese Academy of Sciences
Xiaodong Sun: Shanghai Jiao Tong University School of Medicine
Changhao Bi: Chinese Academy of Sciences
Xueli Zhang: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40655-6

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