Suppr超能文献

基因治疗恢复了视功能并延缓了色素性视网膜炎的 CNGB1(-/-) 小鼠模型的变性。

Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa.

机构信息

Center for Integrated Protein Science Munich, Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.

出版信息

Hum Mol Genet. 2012 Oct 15;21(20):4486-96. doi: 10.1093/hmg/dds290. Epub 2012 Jul 16.

Abstract

Retinitis pigmentosa (RP) is a group of genetically heterogeneous, severe retinal diseases commonly leading to legal blindness. Mutations in the CNGB1a subunit of the rod cyclic nucleotide-gated (CNG) channel have been found to cause RP in patients. Here, we demonstrate the efficacy of gene therapy as a potential treatment for RP by means of recombinant adeno-associated viral (AAV) vectors in the CNGB1 knockout (CNGB1(-/-)) mouse model. To enable efficient packaging and rod-specific expression of the relatively large CNGB1a cDNA (~4 kb), we used an AAV expression cassette with a short rod-specific promoter and short regulatory elements. After injection of therapeutic AAVs into the subretinal space of 2-week-old CNGB1(-/-) mice, we assessed the restoration of the visual system by analyzing (i) CNG channel expression and localization, (ii) retinal function and morphology and (iii) vision-guided behavior. We found that the treatment not only led to expression of full-length CNGB1a, but also restored normal levels of the previously degraded CNGA1 subunit of the rod CNG channel. Both proteins co-localized in rod outer segments and formed regular CNG channel complexes within the treated area of the CNGB1(-/-) retina, leading to significant morphological preservation and a delay of retinal degeneration. In the electroretinographic analysis, we also observed restoration of rod-driven light responses. Finally, treated CNGB1(-/-) mice performed significantly better than untreated mice in a rod-dependent vision-guided behavior test. In summary, this work provides a proof-of-concept for the treatment of rod channelopathy-associated RP by AAV-mediated gene replacement.

摘要

色素性视网膜炎(RP)是一组遗传异质性的严重视网膜疾病,通常导致法定失明。已经发现杆状环核苷酸门控(CNG)通道的 CNGB1a 亚基的突变会导致患者出现 RP。在这里,我们通过杆状细胞特异性启动子和短调控元件的重组腺相关病毒(AAV)载体,在 CNGB1 敲除(CNGB1(-/-))小鼠模型中证明了基因治疗作为 RP 潜在治疗方法的疗效。为了实现相对较大的 CNGB1a cDNA(~4 kb)的高效包装和杆状细胞特异性表达,我们使用了带有短杆状细胞特异性启动子和短调控元件的 AAV 表达盒。在将治疗性 AAV 注射到 2 周龄的 CNGB1(-/-) 小鼠的视网膜下腔后,我们通过分析(i)CNG 通道的表达和定位、(ii)视网膜功能和形态以及(iii)视觉引导行为,评估了视觉系统的恢复情况。我们发现,该治疗不仅导致全长 CNGB1a 的表达,还恢复了先前降解的杆状 CNG 通道的 CNGA1 亚基的正常水平。两种蛋白在杆状细胞外段共定位,并在 CNGB1(-/-) 视网膜的治疗区域内形成规则的 CNG 通道复合物,导致形态学显著保存和视网膜变性的延迟。在视网膜电图分析中,我们还观察到对杆状细胞驱动的光反应的恢复。最后,在杆状细胞依赖性视觉引导行为测试中,接受治疗的 CNGB1(-/-) 小鼠的表现明显优于未接受治疗的小鼠。总之,这项工作为通过 AAV 介导的基因替代治疗与杆状细胞通道病相关的 RP 提供了概念验证。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验