Inherited retinal dystrophies (IRDs) are a group of neurodegenerative disorders, with retinitis pigmentosa (RP) being the most prevalent. IRDs lead to vision loss due to the progressive degeneration of both type of photoreceptors: rods and cones. To date, over 270 pathogenic variants have been associated with IRDs. This high genetic heterogeneity hampers the development of effective therapies. Although the pathogenic mechanisms of these diseases are not fully elucidated, calcium dysregulation and oxidative stress have been described as pathogenic mechanisms contributing to photoreceptor death in IRDs. Recently, ryanodine receptor type 2 (RyR2), one of the main calcium release channels from the endoplasmic reticulum in photoreceptors, has been shown to play a central role in calcium homeostasis and photoreceptor degeneration in animal models of achromatopsia.

Our main objective is to develop an innovative therapy for IRDs, based on a new small molecule, termed MP-004, which normalizes intracellular calcium. We tested the hypothesis that MP-004, a novel ligand of FKBP12 (FK506 binding protein of 12kD), is capable of preserve retinal function and structure by modulating RyR2 activity, in a well-established experimental model of retinitis pigmentosa.