Target Identification and Evaluation of Risk in CPVT2 (TIER-CPVT2)

Catecholaminergic Polymorphic Ventricular Tachycardia Type 2 (CPVT2) is a hereditary heart disease, often linked to the sudden death of very young individuals. It is a rare syndrome that predisposes to fatal cardiac arrhythmias. CPVT2 is associated with mutations in a small protein, Calsequestrin, essential for the coordinated contraction of the heart. Pharmacological treatments and/or the implantation of defibrillators can reduce the risk of fatal events. However, these strategies are not specific to the pathological mechanism, and one in three individuals remains susceptible to sudden arrhythmias. The uncertainty about the specific risk to which these individuals and their families are exposed, makes it urgent to identify and correct the specific Calsequestrin defect.

Preliminary results obtained by Dr. Marabelli, a specialist in protein biochemistry, have already provided the first indications of the existence of two distinct pathological forms of Calsequestrin, which could explain the existence of two different hereditary modalities for CPVT2. The project aims to validate the proposed mechanism through comparison, between two groups of Calsequestrin mutants, of their biochemical characteristics and pathological mechanism. The collaboration between Dr. Marabelli and Prof. Priori's Molecular Cardiology group will validate the molecular hypothesis in vivo, on multiple models of the CPVT2 forms, and assess the specificity of a therapy designed for the first form of CPVT2. The results of this study will identify who can benefit from such treatment, and provide the foundation for the immediate development of a complementary therapeutic strategy for individuals affected by the second form of CPVT2.