A gene therapy and pharmacological therapeutic approach to treat autosomal dominant Catecholaminergic Polymorphic Ventricular Tachycardia: investigation of two novel molecular targets.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease, which is characterized by adrenergically-mediated bidirectional or polymorphic ventricular tachycardia, resulting in a syncope and/or sudden cardiac death in genetically predisposed individuals occurring in the absence of structural cardiac defects. The autosomal dominant form of CPVT (CPVT1) is induced by mutations in the gene encoding the cardiac ryanodine receptor (RYR2), which is a large homotetrameric protein involved in the homeostatic calcium (Ca2+) release from the sarcoplasmic reticulum (SR). The aim of this work is to develop and compare two anti-arrhythmic therapeutic approaches to test different novel molecular targets as potential treatments for CPVT1. First, we designed a gene therapy strategy based on the ectopic overexpression of the Sphingosine-1-Phosphate Receptor 1 (S1PR1), and then we performed a new pharmacological treatment based on the specific inhibition of Calmodulin-dependent protein kinase II (CAMKII).Both strategies are hypothesized to prevent the onset of arrhythmogenic substrates by indirectly modulating the β1-adrenergic receptor signaling pathway.We exploited our knock-in RyR2R4496C/+ CPVT1 animal model to allow for the subsequent and effective comparison by in vivo and in vitro phenotypic and molecular characterization, respectively. In the prospect of advancing both treatments in the pre-clinical context, this study also contributes to the ongoing research of the β1-adrenergic receptor on arrhythmogenesis, which is crucial in the future development of new effective treatments for CPVT.