Dysregulation of cGMP is a pathological hallmark of inherited retinal degenerations (RD) affecting photoreceptors, the sensory cells of the retina. These RDs, including Retinitis Pigmentosa, Lebers Congenital Amaurosis, and Achromatopsia, are major causes of blindness, affecting approximately one in every 2000 individuals worldwide, and remain without effective treatment. In photoreceptors, cGMP is produced by retinal guanylyl cyclase (GC). The two main cGMP targets are cyclic nucleotide gated ion channels (CNGC) and cGMP-dependent protein kinase (PKG). Since attenuation of PKG and CNGC activity can reduce photoreceptor cell death, both proteins constitute potential targets to prevent RD. Recent data suggest that blocking retinal GC may also constitute a viable therapeutic approach.This consortium will study and develop targeted compounds and delivery systems aimed at preventing photoreceptor damage in preclinical disease models. Towards this goal, two SMEs have teamed up with three academic research groups focused on retinal degeneration: the German company BIOLOG specializes on development of cyclic nucleotide based drugs targeting PKG, CNGC, and GC; the Dutch company to-BBB develops systems to deliver drugs across the blood brain/retinal barrier (BBB, BRB, resp.); the groups of V. Marigo (Modena, Italy), P. Ekström (Lund, Sweden), and F. Paquet-Durand (Tübingen, Germany) have a strong and joint collaborative track record of studying photoreceptor degenerative mechanisms as well as on testing and evaluating drug treatment effects. Manufacturing of the most promising drugs fitted to a suitable delivery system will be scaled up towards clinical-size batches and studied towards efficacy, toxicology and off-target effects in model animals. The results of the project will allow the SMEs to further co-develop these drugs towards translation into clinical studies, addressing the high needs of RD patients and the high economic benefit of such therapies.