Retinitis Pigmentosa (RP) often results in legal blindness and is caused by more than 100 genetic mutations, making its development challenging to address all causes with gene therapy. FDA approval of gene therapy for LCA addressing RPE65 mutation has sparked great enthusiasm and hope for developing gene therapy. However, classical gene replacement or gene-editing-based sight-saving therapies are applicable when photoreceptors do not degenerate. Current systems, however, are limited by poor resolution and retinal damage over a period. Most current clinical treatments are primarily focused on slowing down the progression of the disease, as there is neither a cure that can stop the degeneration nor a therapy other than retinal prostheses that can improve vision loss due to retinal degeneration. However, the electrical stimulation devices are invasive and require complex implantation surgeries. We have investigated ultrasound stimulation for the retina as a modality for treating retinal degenerative diseases. However, significant challenges in translating this technology include (i) the requirement of high-intensity ultrasound and (ii) the lack of cell-specific stimulation. By sensitizing specific retinal cells (e.g., retinal ganglion cells that are intact in RP) toward ultrasound using the heterologously-expressed mechanosensitive channel, the sonogenetic stimulation-based approach may provide an alternative therapeutic modality to restore visual function in the degenerated retina. Nanoscope has screened and engineered mechanosensitive channels (EMC) from different microbial species, which upon expression in mammalian cells and retina, allows sonogenetic stimulation by ultrasound with intensity orders of magnitude lower than that required without EMC sensitization. EMC is activated by any mechanical force that causes stretch and deformation of the lipid bilayer, such as stretch, pressure/suction, and ultrasound, as measured by pressure clamp and electrophysiology. RGC-specific EMC delivery combined with external US stimulation has generated restoration of visual function in the RP mice model. In the proposed project, we aim to utilize sonogenetic stimulation using ultrasound array transducers for achieving vision restoration in the photoreceptor-degenerated retina. This goal will be achieved through the following aims: Aim 1: In-vitro assessment of the efficacy of EMC by use of focused ultrasound stimulation, Aim 2: In-vivo assessment of low-power ultrasound stimulation of EMC-sensitized retina, Aim 3: Sonogenetic restoration of vision in a rabbit model of Retinitis Pigmentosa. The success of this proposed project will lead to the realization of a non-invasive sonogenetic combination therapy for vision restoration in retinal degenerative diseases.