In vivo optogenetic stimulation of the primate retina activates the visual cortex after long-term transduction

Abstract

Over the last 15 years, optogenetics has changed fundamental research in neuroscience and is now reaching toward therapeutic applications. Vision restoration strategies using optogenetics are now at the forefront of these new clinical opportunities. But applications to human patients suffering from retinal diseases leading to blindness raise important concerns on the long-term functional expression of optogenes and the efficient signal transmission to higher visual centers. Here, we demonstrate in non-human primates continued expression and functionality at the retina level ∼20 months after delivery of our construct. We also performed in vivo recordings of visually evoked potentials in the primary visual cortex of anesthetized animals. Using synaptic blockers, we isolated the in vivo cortical activation resulting from the direct optogenetic stimulation of primate retina. In conclusion, our work indicates long-term transgene expression and transmission of the signal generated in the macaque retina to the visual cortex, two important features for future clinical applications.

High spatial resolution artificial vision inferred from the spiking output of retinal ganglion cells stimulated by optogenetic and electrical means

“…In laboratory conditions, we and others have reported high spatial and temporal resolution of stimulated RGC activity both for epiretinal electrical (Weitz et al, 2015;Corna et al, 2021) and optogenetic stimulation (Ferrari et al, 2020;Gauvain et al, 2021;Reh et al, 2021;Chaffiol et al, 2022;Khabou et al, 2022). This represents an encouraging result for future vision restoration.…”

Nucleic Acid Delivery Nanotechnologies for In Vivo Cell Programming

“…Previous research has demonstrated that an AAV2based transduction of the ChrimsonR-TdTomato optogene through intravitreal injection in nonhuman primates resulted in sustained functional expression in the retina for up to 20 months. 125 A few Phase I/II clinical trials of retinal optogenetics for visual restoration have recently been completed and demonstrated general safety of the approach. 126 Clinical translation for cardiac optogenetic therapies has not advanced as quickly as retinal optogenetics as gene and light delivery to the heart is more challenging.…”

Gene therapy in hereditary retinal dystrophy

“…A previous study confirmed that in rodents intravitreally injected with an AAV-channelrhodopsin-2 (ChR2) construct, ChR2 can stabilize expression in the retina and rescue visual function[ 59 ]. In a nonhuman primate study, primates ( Macaca fascicularis ) were intravitally injected with an AAV2 vector with ChR2 to stimulate retinal activation after long-term transfection[ 60 ]. Recently, optogenetics was used to treat a blind patient in a phase 1/2a clinical trial.…”