Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

The loss of cone photoreceptor function in retinitis pigmentosa (RP) severely impacts the central and daily vision and quality of life of patients affected by this disease. The loss of cones follows the degeneration of rods, in a manner independent of the causing mutations in numerous genes associated with RP.

We have explored this phenomenon and proposed that the loss of rods triggers a reduction in the expression of rod-derived cone viability factor (RdCVF) encoded by the nucleoredoxin-like 1 (NXNL1) gene which interrupts the metabolic and redox signaling between rods and cones. After providing scientific evidence supporting this mechanism, we propose a way to restore this lost signaling and prevent the cone vision loss in animal models of RP. We also explain how we could restore this signaling to prevent cone vision loss in animal models of the disease and how we plan to apply this therapeutic strategy by the administration of both products of NXNL1 encoding the trophic factor RdCVF and the thioredoxin enzyme RdCVFL using an adeno-associated viral vector. We describe in detail all the steps of this translational program, from the design of the drug, its production, biological validation, and analytical and preclinical qualification required for a future clinical trial that would, if successful, provide a treatment for this incurable disease.

The dominance of rods in the retina of most mammals is the result of an evolutionary constraint known as nocturnal bottleneck [191]. The reasons explaining why, in RP, rods are affected before cones, even in cases of mutations in genes expressed by both types of photoreceptors, is presently unknown. The secondary loss of function of cones is observed irrespective of the type of mutations. The interruption of the metabolic and redox signaling between rods and cones though the loss of expression of RdCVF following rod cell death explains quite well the phenomenon which is initiated by the reduction of cone vision because of the shortening of the cone outer segments [117,118]. Even if this mechanism may not be unique [192], the administration of both products of the NXNL1 gene provides the rational for a therapy aimed at preventing or delaying the loss of central vision in all genetic forms of RP.