etinitis pigmentosa (RP) is a progressive, inherited, monogenic or rarely digenic 1 blinding disease caused by mutations in more than 71 different genes (https://sph.uth.edu/retnet/ sum-dis.htm). It affects more than 2 million people worldwide. With the exception of a gene replacement therapy for one form of early-onset RP caused by mutation in the gene RPE65 (ref. 2 ), there is no approved therapy for RP.Optogenetic vision restoration 3-5 is a mutation-independent approach for restoring visual function at the late stages of RP after vision is lost [6][7][8][9] . The open-label phase 1/2a PIONEER study (ClinicalTrials.gov identifier: NCT03326336; the clinical trial protocol is provided in the Supplementary Text) was designed to evaluate the safety (primary objective) and efficacy (secondary objective) of an investigational treatment for patients with advanced nonsyndromic RP that combines injection of an optogenetic vector (GS030-Drug Product (GS030-DP)) with wearing a medical device, namely light-stimulating goggles (GS030-Medical Device (GS030-MD)). The proof of concept for GS030-DP and the GS030-DP dose used in the PIONEER clinical trial were established in nonhuman primate studies 10,11 .The optogenetic vector, a serotype 2.7m8 (ref. 12 ) adenoassociated viral vector encoding the light-sensing channelrhodopsin protein ChrimsonR fused to the red fluorescent protein tdTomato 13 , was administered by a single intravitreal injection into the worse-seeing eye to target mainly foveal retinal ganglion cells 10 . The fusion protein tdTomato was included to increase the expression of ChrimsonR in the cell membrane 10 . The peak sensitivity of ChrimsonR-tdTomato is around 590 nm (amber color) 13 . We chose ChrimsonR, which has one of the most red-shifted action spectra among the available optogenetic sensors because amber light is safer and causes less pupil constriction 10 than the blue light used to activate many other sensors. The light-stimulating goggles capture images from the visual world using a neuromorphic camera that detects changes in intensity, pixel by pixel, as distinct events 14 . The goggles then transform the events into monochromatic images and project them in real time as local 595-nm light pulses onto the retina (Extended Data Fig. 1). Results Safety of the optogenetic vector and light-stimulating goggles.In this article, we describe the partial recovery of vision in one participant of the PIONEER study. At the inclusion in the study, this 58-year-old male, who was diagnosed with RP 40 years ago, had a visual acuity limited to light perception. The worse-seeing eye was treated with 5.0 × 10 10 vector genomes of optogenetic vector. Both before and after the injection, we performed ocular examinations and assessed the anatomy of the retina based on optical coherence tomography images, color fundus photographs and fundus autofluorescence images taken on several occasions over 15 visits spanning 84 weeks according to the protocol (Extended Data Fig. 2). We monitored potential intraocular inflammation a...

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerative diseases, characterized by the progressive death of rod and cone photoreceptors. A tremendous genetic heterogeneity is associated with the RP phenotype. Most mutations affect rods selectively and, through an unknown pathway, cause the rod cells to die by apoptosis. Cones, on the other hand, are seldom directly affected by the identified mutations, and yet, in many cases, they degenerate secondarily to rods, which accounts for loss of central vision and complete blindness. Many animal models of RP are available and have led to a better understanding of the disease and to the development of therapeutic strategies aimed at curing the specific genetic disorder (gene therapy), slowing down or even stopping the process of photoreceptor degeneration (growth factors or calcium blockers applications, vitamin supplementation), preserving the cones implicated in the central visual function (identification of endogenous cone viability factors) or even replacing the lost cells (transplantation, use of stem or precursor cells). Still, many obstacles will need to be overcome before most of these strategies can be applied to humans. In this review, we describe the different therapeutic strategies being studied worldwide and report the latest results in this field.