The Nuffield Laboratory of Ophthalmology, Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Cell Mol Life Sci. 2021 Feb;78(4):1597-1613. doi: 10.1007/s00018-020-03597-6. Epub 2020 Jul 29.
Optogenetic strategies to restore vision in patients blind from end-stage retinal degenerations aim to render remaining retinal neurons light-sensitive. We present an innovative combination of multi-electrode array recordings together with a complex pattern-generating light source as a toolset to determine the extent to which neural retinal responses to complex light stimuli can be restored following viral delivery of red-shifted channelrhodopsin in the retinally degenerated mouse. Our data indicate that retinal output level spatiotemporal response characteristics achieved by optogenetic gene therapy closely parallel those observed for normal mice but equally reveal important limitations, some of which could be mitigated using bipolar-cell targeted gene-delivery approaches. As clinical trials are commencing, these data provide important new information on the capacity and limitations of channelrhodopsin-based gene therapies. The toolset we established enables comparing optogenetic constructs and stem-cell-based techniques, thereby providing an efficient and sensitive starting point to identify future approaches for vision restoration.
光遗传学策略旨在使晚期视网膜变性致盲的患者恢复视力，使剩余的视网膜神经元对光敏感。我们提出了一种多电极阵列记录与复杂模式生成光源相结合的创新组合，作为一种工具，以确定在视网膜变性小鼠中通过病毒传递红移型通道蛋白后，对复杂光刺激的神经视网膜反应在多大程度上可以恢复。我们的数据表明，光遗传学基因治疗所达到的视网膜输出水平时空反应特征与正常小鼠观察到的特征非常相似，但同样也揭示了重要的局限性，其中一些局限性可以通过双极细胞靶向基因传递方法来减轻。随着临床试验的开始，这些数据为基于通道蛋白的基因治疗的能力和局限性提供了重要的新信息。我们建立的工具集可用于比较光遗传学构建体和基于干细胞的技术，从而为确定未来的视力恢复方法提供了一个高效、敏感的起点。
