한빛사논문
- 조회593
강원대학교
Dong Hyun Jo 1,10, Hyeon-Ki Jang 2,10, Chang Sik Cho 3, Jun Hee Han 4, Gahee Ryu 4, Youngri Jung 4, Sangsu Bae 5,6, Jeong Hun Kim 3,5,7,8,9
1Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
2Division of Chemical Engineering and Bioengineering, College of Art Culture and Engineering, Kangwon National University, Chuncheon 24341, Republic of Korea
3Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea
4Department of Chemistry, Hanyang University, Seoul, Republic of Korea
5Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
6Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea
7Department of Ophthalmology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
8Advanced Biomedical Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
9Institute of Reproductive Medicine and Population, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
10These authors contributed equally.
Corresponding authors: Sangsu Bae, PhD, Jeong Hun Kim, MD, PhD
Abstract
Leber congenital amaurosis (LCA), an inherited retinal degeneration, causes severe visual dysfunction in children and adolescents. In patients with LCA, pathogenic variants, such as RPE65, are evident in specific genes, related to the functions of retinal pigment epithelium and photoreceptors. In contrast to the original Cas9, base editing tools can correct pathogenic substitutions without generation of DNA double-stranded breaks (DSBs). In this study, dual adeno-associated virus (AAV) vectors containing split adenine base editors (ABEs) with trans-splicing intein were prepared for in vivo base editing in retinal degeneration of 12 (rd12) mice, an animal model of LCA, possessing a nonsense mutation of C to T transition in the Rpe65 gene (p.R44X). Subretinal injection of AAV-ABE in retinal pigment epithelial cells of rd12 mice resulted in an A to G transition. The on-target editing was sufficient for recovery of wild-type mRNA, RPE65 protein, and light-induced electrical responses from the retina. Compared with our previous therapeutic editing strategies using Cas9 and prime editing, or with the gene transfer strategy shown in the current study, our results suggest that, considering the editing efficacy and functional recovery, ABEs could be a strong, reliable method for correction of pathogenic variants in the treatment of LCA.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-03-08)
- 국내 연구진
- 의약학 > 응용의학
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