AAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa.
AAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa.
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DOI：
10.1038/s41467-023-40655-6
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发表时间：
2023-08-15
影响因子：
16.6
通讯作者：
Zhang, Xueli
中科院分区：
文献类型：
--
作者：
Wu, Yidong;Wan, Xiaoling;Zhao, Dongdong;Chen, Xuxu;Wang, Yujie;Tang, Xinxin;Li, Ju;Li, Siwei;Sun, Xiaodong;Bi, Changhao;Zhang, Xueli
碱基编辑技术是治疗致病性单核苷酸变异（SNV）的理想解决方案。目前还没有基因编辑疗法被批准用于眼部疾病，如视网膜色素变性（RP）。在这里，我们显示，在rd10小鼠模型中，其携带被鉴定为在人类患者中引起RP突变的SNV，视网膜下递送含有腺嘌呤碱基编辑器的优化的双重腺相关病毒系统以高达49%的效率纠正了神经视网膜中的致病性SNV。光学显微镜检查显示，与未处理的薄的、退化的外核层相比，在处理区域中保留了厚的和坚固的外核层（光感受器）。在治疗的rd10眼睛中检测到大量视网膜电图信号，而对照治疗的眼睛显示最小的信号。水迷宫实验表明，该处理显著改善了视觉引导行为。我们一起构建并验证了用于治疗人类RP的转化治疗解决方案。我们的发现可能会加速基于碱基编辑的基因疗法的发展。碱基编辑技术在治疗致病性单核苷酸变异方面具有巨大潜力。使用双AAV碱基编辑系统，Wu等人恢复了视网膜色素变性小鼠模型的视觉功能。
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. Base editing technology has great potential in treating pathogenic single-nucleotide variations. Using a dual-AAV base editing system, Wu et al. restored visual functions in a mouse model of retinitis pigmentosa.
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作者：
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通讯作者：
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通讯作者：
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