Characterization of patient-specific pacemaker-like iPSC-derived cardiomyocytes for sinus node dysfunction treatment – FENICE

Symptomatic sinus node dysfunction (SND) is the most common bradyarrhythmia and the leading cause for over 500,000 electric pacemaker devices implanted yearly in Europe and U.S. In recent years, an increasing number of mutations affecting ion channels involved in sino?atrial automaticity, including RyR2, HCN4 and CaV1.3, have been reported to underlie inheritable primary SND. Using murin model, we have demonstrated that silencing or inhibiting the G protein gated K+ channel (Girk4) normalizes heart rate and prevents bradyarrhythmia in mouse models of primary SND. Therefore, targeting Girk4 may drastically reduce SND symptoms in patients and significantly improve the quality of life. To further appreciate the patient-specific context and penetrate the genotype/phenotype relationship of SND, FENICE offers to exploit cutting-edge technologies including iPSC, CRISPR/Cas9, siRNA, patient cohort and single cell genomics to generate iPSC-derived pacemaker-like cardiomyocytes and model SND using patient-derived cardiomyocytes harbouring mutations on RyR2, HCN4 and CaV1.3. Primary results indicate our capability to obtain more than 50% of iPSC-derived atrial- and pacemaker-like cardiomyocytes.
FENICE will employ adenoviral vectors to silence IKACh current and evaluate whether it normalizes automaticity in SND patient-derived pacemaker-like cardiomyocytes. Finally, to reach pathophysiological evidences, FENICE will tailor therapeutic strategy in available mouse models of primary SND using adenoviral vectors.
Overall FENICE explores fundamental, clinical and therapeutic aspects of SND in patient-specific cellular and molecular context using cutting-edge technologies. At the interface between basic research and clinical research, FENICE also aims at bringing new personalized medicine tools for cardiovascular diseases. The scientific synergy and physical proximity among the 2 partners are a guarantee for effectiveness and successful outcomes of the project.