Developing gene‐independent approaches for retinal dystrophies

Abstract

Inherited retinal dystrophies (IRDs) display remarkable genetic heterogeneity, with over 300 retinal disease genes mapped and/or identified. Profound vision loss and blindness, often from birth, is a common occurrence in these clinically heterogeneous disease conditions. The therapeutic options for IRDs are currently very limited but recent advancements in understanding mechanisms of retinal degeneration and technological progress paved the way towards development of novel therapies. Much progress has been made in moving from gene discovery to gene therapy. However, the genetic heterogeneity of IRDs represents a significant challenge for development of gene therapy.Many studies from our group have demonstrated that the survival of cones (responsible for diurnal and high‐resolution vision) depends on the presence of rods (responsible for vision at low light levels) that secrete a diffusible trophic factor identified as rod‐derived cone viability factor (RdCVF). The discovery of RdCVF, of its receptor and mechanism of action, and the demonstration of its mutation‐independent therapeutic potential in several animal models of IRDs paved the way to the development (with the start‐up company Sparing Vision) of RdCVF neuroprotective gene therapy that entered in clinical trial in 2023.IRDs destroy photoreceptors but leave intact and functional a significant number of inner retinal cells. Using viral vectors, light‐sensitive microbial opsins can be expressed in these remaining cells, making possible their conversion into ‘artificial photoreceptors’. Our group in Paris, together with Botond Roska (IOB, Basel) and the biotech company GenSight, demonstrated that this technology, named optogenetics, can restore vision in secondary retinal neurons which can survive years after the degeneration of photoreceptors. Our groups established the foundation for the first‐in‐man clinical trial (NCT03326336) with the photoactivatable optogene ChrimsonR (developed by Ed Boyen at MIT) delivered in the eye via adeno‐associated viral vectors and electronic goggles to intensify the light and provide adaptation. We demonstrated (Nat Med 2021) that optogenetics is a remarkably effective way to restore partial vision and provide useful vision restoration in blind people.Gene‐independent approaches such as neuroprotection and optogenetics would allow for the treatment of a broad spectrum of retinal dystrophies, even at advanced stages of disease, giving hope for vision rescue and vision restoration to approximately 2 million people with IRDs worldwide.