Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.

IF 5.4 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Yidong Wu, Tianyuan Zhao, Yazhi Wang, Ting Zhang, Chenyue Hang, Yafang Wang, Yang Liu, Zhixuan Chen, Jieqiong Chen, Tong Li, Junran Sun, Huixun Jia, Lei Zhang, Fenghua Wang, Xiaoling Wan, Xiaodong Sun
{"title":"Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.","authors":"Yidong Wu, Tianyuan Zhao, Yazhi Wang, Ting Zhang, Chenyue Hang, Yafang Wang, Yang Liu, Zhixuan Chen, Jieqiong Chen, Tong Li, Junran Sun, Huixun Jia, Lei Zhang, Fenghua Wang, Xiaoling Wan, Xiaodong Sun","doi":"10.1038/s43856-025-01108-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Retinitis pigmentosa (RP) is a leading cause of blindness affecting 2 million people worldwide. Mutations in cyclic nucleotide-gated channel alpha 1 (CNGA1) account for 2-8% of autosomal recessive RP with no available treatment. Here we further evaluate our previously developed Cnga1<sup>-/-</sup> mouse model. We aim to present detailed phenotype data and assess the therapeutic efficacy of gene augmentation in this model.</p><p><strong>Methods: </strong>The retinal function and structure of Cnga1<sup>-/-</sup> mice were accessed from postnatal month 1 to 6. AAV8-hRHO-mCnga1 was constructed and delivered into the subretinal space of 2-week-old Cnga1<sup>-/-</sup> mice. Retinal function, photoreceptor survival, and vision-guided behavior were evaluated following treatment.</p><p><strong>Results: </strong>Here we show that Cnga1<sup>-/-</sup> mice have a similar phenotype to human patients, characterized by an early loss of rod-mediated retinal function and progressive photoreceptor degeneration, which is nearly complete by 6 months of age. Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months. Treated mice also show improved performance in a vision-guided behavior test. RNA-seq reveals upregulation of genes associated with phototransduction.</p><p><strong>Conclusions: </strong>To the best of our knowledge, this work demonstrates for the first time that a gene augmentation approach can restore vision and preserves photoreceptors in an animal model of CNGA1-RP. These findings pave the way for future development of gene augmentation therapy for patients with CNGA1-RP.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"384"},"PeriodicalIF":5.4000,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405462/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Communications medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s43856-025-01108-x","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Retinitis pigmentosa (RP) is a leading cause of blindness affecting 2 million people worldwide. Mutations in cyclic nucleotide-gated channel alpha 1 (CNGA1) account for 2-8% of autosomal recessive RP with no available treatment. Here we further evaluate our previously developed Cnga1-/- mouse model. We aim to present detailed phenotype data and assess the therapeutic efficacy of gene augmentation in this model.

Methods: The retinal function and structure of Cnga1-/- mice were accessed from postnatal month 1 to 6. AAV8-hRHO-mCnga1 was constructed and delivered into the subretinal space of 2-week-old Cnga1-/- mice. Retinal function, photoreceptor survival, and vision-guided behavior were evaluated following treatment.

Results: Here we show that Cnga1-/- mice have a similar phenotype to human patients, characterized by an early loss of rod-mediated retinal function and progressive photoreceptor degeneration, which is nearly complete by 6 months of age. Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months. Treated mice also show improved performance in a vision-guided behavior test. RNA-seq reveals upregulation of genes associated with phototransduction.

Conclusions: To the best of our knowledge, this work demonstrates for the first time that a gene augmentation approach can restore vision and preserves photoreceptors in an animal model of CNGA1-RP. These findings pave the way for future development of gene augmentation therapy for patients with CNGA1-RP.

基因增强疗法在cnga1视网膜色素变性小鼠模型中恢复视力并保留光感受器。
背景:色素性视网膜炎(RP)是全球影响200万人失明的主要原因。环核苷酸门控通道α 1 (CNGA1)突变占常染色体隐性RP的2-8%,没有可用的治疗。在这里,我们进一步评估了我们之前开发的Cnga1-/-小鼠模型。我们的目标是在该模型中提供详细的表型数据并评估基因增强的治疗效果。方法:从出生后1 ~ 6个月观察Cnga1-/-小鼠的视网膜功能和结构。构建AAV8-hRHO-mCnga1并将其递送至2周龄Cnga1-/-小鼠视网膜下间隙。治疗后评估视网膜功能、光感受器存活和视觉引导行为。结果:在这里,我们发现Cnga1-/-小鼠具有与人类患者相似的表型,其特征是早期失去杆介导的视网膜功能和进行性光感受器变性,这几乎在6个月大时完成。基因增强治疗导致CNGA1蛋白的正确表达,视网膜功能的持续恢复和光感受器的长期保存至少9个月。在一项视觉引导行为测试中,接受治疗的老鼠也表现出更好的表现。RNA-seq显示与光转导相关的基因上调。结论:据我们所知,这项工作首次证明了基因增强方法可以恢复CNGA1-RP动物模型的视力并保留光感受器。这些发现为CNGA1-RP患者基因增强治疗的未来发展铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信