Optogenetic gene therapy holds promise to restore high-quality vision in blind patients and recently reached clinical trials. Although the ON-bipolar cells, the first retinal interneurons, make the most attractive targets for optogenetic vision restoration, they have remained inaccessible to human gene therapy due to the lack of a robust cell-specific promoter. We describe the design and functional evaluation of 770En_454P(hGRM6), a human GRM6 gene-derived, short promoter that drives strong and highly specific expression in both the rod- and cone-type ON-bipolar cells of the human retina. Expression also in cone-type ON-bipolar cells is of importance, since the cone-dominated macula mediates high-acuity vision and is the primary target of gene therapies. 770En_454P(hGRM6)-driven middle-wave opsin expression in ON-bipolar cells achieved lasting restoration of high visual acuity in the rd1 mouse model of late retinal degeneration. The new promoter enables precise manipulation of the inner retinal network and paves the way for clinical application of gene therapies for high-resolution optogenetic vision restoration, raising hopes of significantly improving the life quality of people suffering from blindness.

光遗传基因疗法有望恢复盲人患者的高质量视力，并已进入临床试验。尽管ON-双极细胞是第一个视网膜中间神经元，是光遗传学视力恢复的最有吸引力的靶标，但由于缺乏强大的细胞特异性启动子，它们仍无法用于人类基因治疗。我们描述了770En_454P（h GRM6）的设计和功能评估，770En_454P（h GRM6基因衍生的，短启动子，在人视网膜的杆状和锥状ON双极细胞中都驱动强而高度特异性的表达。在视锥型ON双极细胞中表达也很重要，因为视锥为主的黄斑介导了高敏视力，并且是基因治疗的主要目标。770En_454P（h GRM6驱动的中波视蛋白在双极细胞中的表达在视网膜后期变性的rd1小鼠模型中实现了高视力的持久恢复。新的启动子能够精确地控制内部视网膜网络，并为基因治疗在高分辨率光遗传学视力恢复中的基因治疗的临床应用铺平了道路，从而为大大改善盲人生活质量带来了希望。