Red‐shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina

• Published in: EMBO molecular medicine Vol. 8; no. 11; pp. 1248 - 1264
• Main Authors: Sengupta, Abhishek, Chaffiol, Antoine, Macé, Emilie, Caplette, Romain, Desrosiers, Mélissa, Lampič, Maruša, Forster, Valérie, Marre, Olivier, Lin, John Y, Sahel, José‐Alain, Picaud, Serge, Dalkara, Deniz, Duebel, Jens
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2016; EMBO Press; Wiley Open Access; John Wiley and Sons Inc; Springer Nature
• Subjects: Animals; channelrhodopsin; Cortex; Dependovirus - genetics; EMBO16; EMBO27; Experiments; Genetic Therapy - methods; Genetic Vectors; Human health and pathology; Humans; Lentivirus - genetics; Life Sciences; Light; Macaca; Membranes; Mice; Microscopy; optogenetics; Photoreceptors; Phototherapy - methods; primate; Research Article; Retina; Retina - physiology; Retinal degeneration; Retinal Degeneration - therapy; Retinal ganglion cells; Rhodopsin - genetics; Rhodopsin - metabolism; Sensory Organs; Transduction, Genetic; Treatment Outcome; vision restoration; primate; vision restoration; channelrhodopsin; retina; optogenetics; Gene Therapy & Genetic Disease
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201505699

Targeting the photosensitive ion channel channelrhodopsin‐2 (ChR2) to the retinal circuitry downstream of photoreceptors holds promise in treating vision loss caused by retinal degeneration. However, the high intensity of blue light necessary to activate channelrhodopsin‐2 exceeds the safety threshold of retinal illumination because of its strong potential to induce photochemical damage. In contrast, the damage potential of red‐shifted light is vastly lower than that of blue light. Here, we show that a red‐shifted channelrhodopsin (ReaChR), delivered by AAV injections in blind rd1 mice, enables restoration of light responses at the retinal, cortical, and behavioral levels, using orange light at intensities below the safety threshold for the human retina. We further show that postmortem macaque retinae infected with AAV‐ReaChR can respond with spike trains to orange light at safe intensities. Finally, to directly address the question of translatability to human subjects, we demonstrate for the first time, AAV‐ and lentivirus‐mediated optogenetic spike responses in ganglion cells of the postmortem human retina. Synopsis A red‐shifted channelrhodopsin (ReaChR) was targeted to retinal ganglion cells using three models in parallel: mouse, macaque, and human. Safe orange illumination was able to trigger light responses in all three systems. The red‐shifted channelrhodopsin ReaChR restored light responses at the retinal, cortical, and behavioral levels in blind rd1 mice, using light intensities below the safety limit for the human retina. Optogenetic light responses were demonstrated in explanted postmortem macaque and human retina, infected ex vivo with viral vectors encoding ReaChR. The study presents the first electrophysiological recordings of optogenetic light responses in ganglion cells obtained directly from the human fovea as well as the far peripheral human retina. Graphical Abstract A red‐shifted channelrhodopsin (ReaChR) was targeted to retinal ganglion cells using three models in parallel: mouse, macaque, and human. Safe orange illumination was able to trigger light responses in all three systems.