Transgenic Expression of Cacna1f Rescues Vision and Retinal Morphology in a Mouse Model of Congenital Stationary Night Blindness 2A (CSNB2A).
Transgenic Expression of Cacna1f Rescues Vision and Retinal Morphology in a Mouse Model of Congenital Stationary Night Blindness 2A (CSNB2A).
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DOI：
10.1167/tvst.9.11.19
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发表时间：
2020-10
影响因子：
3
通讯作者：
Bech-Hansen NT
中科院分区：
文献类型：
--
作者：
Waldner DM;Ito K;Chen LL;Nguyen L;Chow RL;Lee A;Rancourt DE;Tremblay F;Stell WK;Bech-Hansen NT
先天性静止性夜盲2A（Congenital stationary night blindness 2A，CSNB 2A）是一种遗传性视网膜疾病，其特征是视力差、眼球震颤、斜视和其他视网膜功能障碍的体征，这些症状是由编码钙通道CaV1.4的成孔亚基的基因Cacna 1f突变引起的。CSNB 2A的小鼠模型已经表明，导致这种疾病的突变会有害地影响光感受器及其与二级神经元的突触。本研究旨在评估Cacna 1f的转基因表达是否可以在CSNB 2A的Cacna 1f-KO模型中挽救形态和视觉功能。转基因小鼠品系的策略性创建、育种和使用允许CCNB 2A模型中Cacna 1f的Cre驱动的视网膜特异性表达。用免疫组织化学方法在视网膜全标本或横切片中研究转基因表达和视网膜形态学。视动反应（OKR）分析和视网膜电图（ERG）评估视功能。镶嵌，产前表达的Cacna 1f在其他Cacna 1f-KO视网膜足以挽救一些视觉功能。免疫组织化学分析表明，野生型感光细胞和突触形态与Cacna 1f的转基因表达的部分。本报告描述了一种新的系统Cre诱导的Cacna 1f表达的Cacna 1f-KO小鼠模型的CSNB 2A，并提供了临床前的证据，在治疗CSNB 2A的基因治疗的潜在用途。这些数据在CSNB 2A的治疗中具有相关性，并且在理解如何在光感受器已经丢失的视网膜中实现光感受器整合中具有相关性，例如视网膜色素变性、年龄相关性黄斑变性和其他退行性疾病。
Congenital stationary night blindness 2A (CSNB2A) is a genetic retinal disorder characterized by poor visual acuity, nystagmus, strabismus, and other signs of retinal dysfunction resulting from mutations in Cacna1f—the gene coding for the pore-forming subunit of the calcium channel CaV1.4. Mouse models of CSNB2A have shown that mutations causing the disease deleteriously affect photoreceptors and their synapses with second-order neurons. This study was undertaken to evaluate whether transgenic expression of Cacna1f could rescue morphology and visual function in a Cacna1f-KO model of CSNB2A. Strategic creation, breeding and use of transgenic mouse lines allowed for Cre-driven retina-specific expression of Cacna1f in a CSNB2A model. Transgene expression and retinal morphology were investigated with immunohistochemistry in retinal wholemounts or cross-sections. Visual function was assessed by optokinetic response (OKR) analysis and electroretinography (ERG). Mosaic, prenatal expression of Cacna1f in the otherwise Cacna1f-KO retina was sufficient to rescue some visual function. Immunohistochemical analyses demonstrated wild-type-like photoreceptor and synaptic morphology in sections with transgenic expression of Cacna1f. This report describes a novel system for Cre-inducible expression of Cacna1f in a Cacna1f-KO mouse model of CSNB2A and provides preclinical evidence for the potential use of gene therapy in the treatment of CSNB2A. These data have relevance in the treatment of CSNB2A and in understanding how photoreceptor integration might be achieved in retinas in which photoreceptors have been lost, such as retinitis pigmentosa, age-related macular degeneration, and other degenerative conditions.
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