Restoring vision in blind patients: From optogenetic to sonogenetic therapies

Abstract

AbstractVisual restoration is certainly the greatest challenge for brain‐machine interfaces with the high pixel number and high refreshing rate. In the recent year, we brought retinal prostheses and optogenetic therapy up to successful clinical trials. Optogenetics relies on the expression of a microbial opsin in residual neurons by gene therapy. These strategies can provide some vision in blind patients with diseases of photoreceptors such as retinal dystrophies or age‐related macular degeneration. They can reintroduce some information in at the retinal level by activating residual neurons after the loss of photoreceptors. For patients with optic nerve atrophy as in glaucoma and diabetic retinopathy, visual restoration requires the direct activation of the visual cortex. However, cortical prostheses have shown efficacy for limited periods of time and limited pixel numbers.In the present project, we are investigating a novel approach to restore vision at the cortical level with sonogenetic therapy. This approach relies on expressing an ultrasound‐sensitive ionic channel in cortical neurons to imprint images at this level by ultrasound stimulations.The Mscl ionic channel fused to the tdTomato reporter gene was expressed in the visual cortex of rats following a cortical AAV injection. The channel expression was indicated by the red fluorescence of tdTomato. Recording with penetrating electrodes indicated responses to cortical ultrasound stimulation with a high temporal resolution but a shorter latency than natural visual responses. In the absence of AAV injection, the visual cortex was not responsive to ultrasounds. Moving the ultrasound stimulator moved the activated area as indicated by Ecog electrode array recording. Finally, mice having learned to associate a flash of light to a water delivery responded similarly to an ultrasound cortical stimulation if the MscL protein was expressed in their cortex.These results indicate that the MscL channel induces an ultrasound sensitivity of cortical neurons generating a cortical activations with a spatiotemporal resolution suitable for vision restoration and perceived as phosphenes. Further studies will have to demonstrate true vision of forms by this sonogenetic approach prior to a clinical translation.