Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Vision Science Graduate Group, University of California, Berkeley, Berkeley, CA 94720, USA.
Neuron. 2014 Feb 19;81(4):800-13. doi: 10.1016/j.neuron.2014.01.003.
Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. Here, we report a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight. A single intraocular injection of DENAQ photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated photoreceptors. DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD.
色素性视网膜炎（RP）和年龄相关性黄斑变性（AMD）是由杆状细胞和锥状细胞退化引起的致盲性疾病，导致视觉系统的其余部分无法对光做出反应。在这里，我们报告了一种名为 DENAQ 的化学光开关，它可以恢复对类似于普通日光强度的白光的视网膜反应。单次眼内注射 DENAQ 可使盲眼视网膜感光数天，在没有毒性的情况下恢复电生理和行为反应。在具有功能、无功能或退化的杆状细胞和锥状细胞的小鼠品系上进行的实验表明，DENAQ 仅在感光细胞退化的视网膜中有效。DENAQ 赋予超极化激活内向电流的光敏感性，该电流在退化的视网膜中增强，从而实现对视网膜神经节细胞放电的光控。可接受的光敏感性、有利的光谱敏感性以及对病变组织的选择性靶向作用，使 DENAQ 成为晚期 RP 和 AMD 患者视力恢复的主要候选药物。
