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

Abhishek Sengupta (1) , Antoine Chaffiol (1) , Emilie Macé (1) , Romain Caplette (1) , Mélissa Desrosiers (1) , Maruša Lampič (1) , Valérie Forster (1) , Olivier Marre (1) , John y Lin (2) , José-Alain Sahel (3, 1) , Serge Picaud (1) , Deniz Dalkara (1) , Jens Duebel (1)

1 Institut de la Vision
2 UTAS - University of Tasmania [Hobart, Australia]
3 CHNO - Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts

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 post-mortem human retina.

Mots clés: channelrhodopsin; optogenetics; primate; retina; vision restoration; Gene Therapy & Genetic Disease

Domaines: Organes des sens

Abhishek Sengupta, Antoine Chaffiol, Emilie Macé, Romain Caplette, Mélissa Desrosiers, et al.. Red‐shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina. EMBO Molecular Medicine, 2016, pp.e201505699. ⟨10.15252/emmm.201505699⟩. ⟨hal-01375637⟩