Ryanodine receptor (RyR)-related channelopathies are a heterogeneous group of disorders driven by disrupted intracellular Ca²⁺ signaling, with RyR1–3 dysfunction implicated in muscular dystrophies, arrhythmias, neurodegeneration, retinal degeneration, metabolic disease, and ageing. Retinitis pigmentosa (RP) and catecholaminergic polymorphic ventricular tachycardia (CPVT) exemplify RyR2-associated diseases that, despite affecting different tissues, share core mechanisms of calcium dyshomeostasis and oxidative stress, leading to photoreceptor loss and life-threatening ventricular arrhythmias, respectively, in the absence of curative therapies.
This thesis tests whether stabilizing the FKBP/RyR interaction and lowering oxidative stress can blunt this shared pathological cascade. To this end, we evaluated MP compounds—small 1,3-triazole molecules designed to bind FKBP12 and stabilize the FKBP12/RyR complex—with MP-004 showing antioxidant effects and restoration of the FKBP12.6/RyR2 interaction in 661W cells and the rd10 RP mouse model, preserving photoreceptor viability and function. In parallel, MP-001 reduced arrhythmic phenotypes and improved functional alterations in HEK293 cells expressing mutant RyR2 and in CPVT mouse models. Collectively, these results support MP-004 and MP-001 as promising preclinical candidates for RP and CPVT, respectively, and advance a RyR-modulation strategy for two severe, currently untreatable genetic disorders.