FROM MOUSE TO MAN, USING PHYSIOLOGY TO DEVELOP A GENE-SPECIFIC MANAGEMENT OF LETHAL LQT3 VARIANT OF LONG QT SYNDROME

The Long QT Syndrome (LQTS), a leading cause of sudden cardiac death in the young, is an inherited disorder characterized by QT interval prolongation on the electrocardiogram, and by the occurrence of life-threatening arrhythmias (syncope, cardiac arrest, and sudden death). The 3 most common genetic variants of LQTS are LQT1 and LQT2 (caused by mutations affecting cardiac potassium currents), and LQT3 (caused mutations affecting the cardiac sodium channel). Whereas LQT1 and LQT2 patients are very well protected by available therapies, LQT3 patients appear to be less protected and suffer major cardiac events despite therapy. As sudden death often is their first symptom there is a growing tendency to implant all LQT3 patients, even very young and asymptomatic, with an implantable cardioverter defibrillator, a device able to recognise and treat ventricular arrhythmias, but often associated with major negative consequences for quality of life. This short overview clarifies why there is an unmet and pressing need to develop more specific and effective therapeutic approaches for the prevention of sudden death in LQT3 patients and to identify clinical patterns that might help in risk stratification. We have available a strain of mice carriers of a important mutation causing LQT3 (deltaKPQ): this animal model, showing clinical features extremely similar to those observed in LQT3 patients, represents an invaluable pre-clinical tool for therapeutic validation. Our aim is to develop small molecules of RNA, that once delivered to the heart through a specific virus, will be able to correct the genetic defect responsible for the disease. Additionally, we are following a large family with the deltaKPQ mutation and with a devastatingly high incidence of sudden cardiac death and cardiac arrest; in the case of successful experimental results there will be a rapid opportunity, with appropriate safety measures, for clinical verification of the exciting possibility of curing LQT3.