NATURAL IMAGE ENCODING IN OPTOGENETIC VISION WITH CHREEF

Optogenetics offers a disease-agnostic strategy to restore vision in retinal degeneration by introducing light‑sensitive proteins into surviving retinal cells. While early clinical studies show feasibility [1], progress remains limited by the high light intensities required for many typically applied opsins, incomplete understanding of natural visual encoding, and absence of pathway segregation when targeting retinal ganglion cells (RGCs), constraining broader clinical advancement.

We aim to (1) characterise optogenetically evoked responses of RGCs expressing ChReef, a recently engineered variant of ChRmine designed for efficient and sustained optogenetic control [2]. We then aim to (2) compare the sensitivity and natural image responses mediated by ChR2 and ChReef, and to (3) develop stimulation strategies that compensate for the loss of intrinsic retinal computations in the treated retina.

We record RGC activity in ex-vivo mouse retinal preparations using multi-electrode arrays. The retinal degeneration (rd1) mouse model of retinopathy received intravitreal injections to drive ChReef expression in RGCs. For the ChR2 group, transgenic mice expressing ChR2 in RGCs were used.

ChReef‑expressing RGCs showed reliable responses to green‑light stimulation with both full‑field light and natural images. With ChReef, RGCs were activated at significantly lower light levels compared to ChR2. We are currently characterising the spatiotemporal response properties to natural and modified images, driven by ChReef and ChR2. Our preliminary results support that ChReef has a strong potential for safer optogenetic vision restoration with comparatively low light intensities.

[1] Sahel et al. (2021). Nat. Med. 27:1223-1229.

[2] Alekseev et al. (2025). Nat. Biomed. Eng.