The two types of photoreceptor, rods and cones, play distinct and specialized roles in vertebrate vision. While rods are numerically dominant in most mammals, their sole role is to perceive light in very dark environments. Their function is saturated, and they are therefore inoperable during the day, or as soon as illumination rises above the threshold of half-light. It is therefore the cones that perform the most important, and therefore essential, visual function, enabling us to perceive shapes and colors. They are entirely responsible for visual acuity. In primates, cones are grouped together in the center of the retina, the fovea, which is the point of visual fixation.
Hereditary retinal degeneration is an incurable pathology leading to blindness. These diseases affect 40,000 patients in France and over a million worldwide. Retinopathy pigmentosa, the most frequent form of these diseases, progresses in two stages: the first phase corresponds to the loss of the rods, which die by apoptosis, followed by the death of the cones, which cannot survive without the rods. The existence of this link between the two types of photoreceptor is at the origin of the therapeutic strategy we are working on. Mutations in 58 different genes are individually responsible for retinopathy pigmentosa, which progresses from a mild loss of night vision to blindness resulting from the loss of central vision, that of the cones. We have identified one of the products of the Nucleoredoxin-like 1 (NXNL1) gene as the survival factor produced and secreted by the rods and necessary for the survival of the cones. The study of the mechanism of action of this viability factor, called Rod-derived Cone Viability Factor (RdCVF), is highly original in that it prevents cone death by stimulating their energy metabolism - the energy required to maintain a photoreceptor cell structure in which the light-capturing molecules opsins are embedded. RdCVF accelerates the entry of glucose into cones via a receptor protein on their surface, glucose which is metabolized by aerobic glycolysis, a use of glucose generally reserved for rapidly dividing cells such as cancer cells. Rod death, the direct result of the disease-causing mutation, leads to a loss of RdCVF expression, a reduction in the energy available to cones to maintain this structure, and hence the presence of opsins, resulting in blindness. Our aim is therefore to restore RdCVF expression by gene therapy to prevent loss of central vision by maintaining cone function.
