Restoration of Vision with Ectopic Expression of Human Rod Opsin.
Restoration of Vision with Ectopic Expression of Human Rod Opsin.
复制标题
DOI：
10.1016/j.cub.2015.07.029
复制
发表时间：
2015-08-17
期刊：
影响因子：
--
通讯作者：
Lucas RJ
中科院分区：
文献类型：
--
作者：
Cehajic-Kapetanovic J;Eleftheriou C;Allen AE;Milosavljevic N;Pienaar A;Bedford R;Davis KE;Bishop PN;Lucas RJ
许多视网膜营养不良导致光感受器丧失，但内部视网膜神经元可以存活，使它们可能适合新兴的光遗传学疗法。在这里，我们表明，异位表达的人视杆细胞视蛋白，由非选择性或ON双极细胞特异性启动子驱动，可以在天然光感受器外发挥作用，并恢复晚期视网膜变性小鼠模型的视觉功能。视网膜外植体和视觉丘脑的电生理记录显示，在处理小鼠中，由简单的光脉冲、亮度增加和自然电影引起的放电（增加和减少）发生变化。这些反应可以在生理范围内的光强度下引发，并且基本上低于其他光遗传学策略所需的光强度。具有由ON-双极特异性启动子驱动的视杆视蛋白表达的小鼠在自然室内环境典型的对比度和照度（100 - 100勒克斯）水平下对亮度、闪烁、粗糙空间图案和自然电影元素的增加显示出行为反应。这些数据表明，病毒介导的人视杆视蛋白的异位表达可以在自然观察条件下和中等光强度下恢复视力。鉴于采用人类蛋白质的固有优势，这种干预的简单性和恢复的视力质量，我们建议视杆视蛋白值得考虑作为治疗晚期视网膜变性患者的光遗传学致动器。异位的人视杆视蛋白在晚期视网膜变性中恢复视觉功能视杆视蛋白比目前的光遗传学策略具有更高的敏感性视杆视蛋白处理的动物对空间刺激、闪烁和自然场景作出反应作为通常在视网膜组织中发现的人类蛋白质，临床障碍被最小化Cehajic-Kapetanovic等人显示异位表达的人视杆视蛋白在晚期视网膜变性的小鼠模型中恢复视力。恢复视力的质量与替代方法相比是有利的，特别是在敏感性方面，并且使用天然人类蛋白质减少了未来临床试验的障碍。
Many retinal dystrophies result in photoreceptor loss, but the inner retinal neurons can survive, making them potentially amenable to emerging optogenetic therapies. Here, we show that ectopically expressed human rod opsin, driven by either a non-selective or ON-bipolar cell-specific promoter, can function outside native photoreceptors and restore visual function in a mouse model of advanced retinal degeneration. Electrophysiological recordings from retinal explants and the visual thalamus revealed changes in firing (increases and decreases) induced by simple light pulses, luminance increases, and naturalistic movies in treated mice. These responses could be elicited at light intensities within the physiological range and substantially below those required by other optogenetic strategies. Mice with rod opsin expression driven by the ON-bipolar specific promoter displayed behavioral responses to increases in luminance, flicker, coarse spatial patterns, and elements of a natural movie at levels of contrast and illuminance (≈50–100 lux) typical of natural indoor environments. These data reveal that virally mediated ectopic expression of human rod opsin can restore vision under natural viewing conditions and at moderate light intensities. Given the inherent advantages in employing a human protein, the simplicity of this intervention, and the quality of vision restored, we suggest that rod opsin merits consideration as an optogenetic actuator for treating patients with advanced retinal degeneration. Ectopic human rod opsin restores visual functions in advanced retinal degeneration Rod opsin has greater sensitivity than current optogenetic strategies Rod opsin-treated animals respond to spatial stimuli, flicker, and natural scenes As a human protein ordinarily found in retinal tissue, barriers to clinic are minimized Cehajic-Kapetanovic at al. show that ectopically expressed human rod opsin restores vision in a mouse model of advanced retinal degeneration. The quality of the restored vision compares favorably, especially in terms of sensitivity, with alternative approaches, and using a native human protein reduces barriers to future clinical trials.