A synthetic opsin restores vision in patients with severe retinal degeneration.

Abstract

Inherited Retinal degenerations are the leading cause of blindness worldwide, and in advanced stages, cell loss makes gene replacement ineffective. Optogenetics offers a therapeutic opportunity to restore vision by photo-sensitizing remaining retinal neurons. However, current opsins are kinetically slow, partially activated in ambient light, unresponsive to different light colors, and target low-resolution retinal cell circuits. To overcome these limits, we engineered a synthopsin made of three selectively mutated non-mammalian proteins to achieve a broadband Multi-Characteristic Opsin. The synthopsin was packaged into an optimized AAV2 gene therapy vector that targets human retinal bipolar cells. In an investigator-initiated, open-label study, four blind retinitis pigmentosa patients with ABCA4 variants received a single intravitreal gene therapy injection. Noninvasive imaging confirmed retinal gene expression via a fluorescent reporter protein. Patients showed improvement in vision, shape discrimination, and mobility through 52 weeks. There were no significant safety issues despite what is likely one of the most synthetic, non-mammalian proteins ever expressed in a human. This is the first report of a gene monotherapy that can restore vision in blind patients in a mutation-independent manner utilizing an optogenetics technology platform.