Using Virtual Patients to Predict Perceptual Outcomes for Optogenetic Sight Recovery Technologies

Abstract

Optogenetics is emerging as a powerful approach for partial vision restoration, with at least three ongoing clinical trials in humans testing novel light-sensitive proteins (opsins) in patients with inherited retinal degenerative disorders. These therapies aim to restore light responsiveness by introducing opsins into surviving retinal cells, such as bipolar or ganglion cells, enabling them to generate neural activity in response to visual stimuli. One ongoing difficulty in selecting promising opsins for clinical development is that there is no way to predict patient perceptual outcomes from optogenetically evoked neural activity as measured ex vivo. Here, we introduce a virtual patient framework that quantitatively links the sensitivity and speed of opsin-mediated retinal responses to predicted patient outcomes, and show how this framework can predict temporal contrast sensitivity functions - a well-established measure of perceptual performance - from microbial opsin photocurrent responses. Our simulations demonstrate that opsin sensitivity and kinetics jointly determine perceptual outcomes, and that enhancing sensitivity at the expense of temporal resolution can degrade the perception of fast-moving stimuli. This computational platform provides a generalizable tool for comparing and selecting the most effective opsins for clinical translation, thereby guiding the design and optimization of next-generation sight restoration strategies.