Red-shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina.
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.
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Abhishek
A
Sengupta
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Antoine
A
Chaffiol
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Emilie
E
Macé
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Romain
R
Caplette
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Mélissa
M
Desrosiers
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Maruša
M
Lampič
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Valérie
V
Forster
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Olivier
O
Marre
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
John Y
JY
Lin
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.|Hôpital des Quinze-Vingts, Paris, France.
José-Alain
JA
Sahel
INSERM U968, Paris, France.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Serge
S
Picaud
INSERM U968, Paris, France jens.duebel@inserm.fr deniz.dalkara@gmail.com.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Deniz
D
Dalkara
INSERM U968, Paris, France jens.duebel@inserm.fr deniz.dalkara@gmail.com.|Sorbonne Universités UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France.|CNRS UMR_7210, Paris, France.
Jens
0000-0002-9906-5597
J
Duebel
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008027:Light; D008251:Macaca; D051379:Mice; D010789:Phototherapy / Q000379:methods*; D012160:Retina / Q000502:physiology*; D012162:Retinal Degeneration / Q000628:therapy*; D012243:Rhodopsin / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D016896:Treatment Outcome
D012243:Rhodopsin
channelrhodopsin; optogenetics; primate; retina; vision restoration
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