From Mouse to man, using physiology to develop a gene-specific management of lethal LQT3 variant of Long QT Syndrome
ProjectThe long QT Syndrome (LQTS) is a leading cause of sudden cardiac death in the young. Even though beta-blocker therapy is effective in most patients, almost 50% of those with mutations on the sodium channel gene
SCN5A
(LQT3 patients) are not protected by therapy and 15% have cardiac arrest or sudden death.
Our primary objective is to develop a gene therapy approach in a population of knock-in mice, heterozygous for the relatively common deltaKPQ mutation on
SCN5A
, that shares the same phenotype of deltaKPQ LQT3 patients.
The aim of the project are: 1) molecular correction of the genetic defect in the murine model through gene therapy; 2) verification of the efficacy of gene-therapy; 3) completion of the phenotypic characterization of the deltaKPQ mice and identification of novel predictors of risk for cardiac events; 4) confirmation in LQT3 patients of the same markers of risk identified in mice.
According to the aims we will:1) knockdown the
SCN5A
−deltaKPQ allele in transgenic mice; 2) verify the efficacy of gene-therapy by comparing molecular (RNA and protein expression), cellular (sodium current, action potential duration), and clinical parameters (ECG, arrhythmic events, response to pharmacological and non-pharmacological interventions), before and after correction of the genetic defect; 3) identify by telemetric ECG monitoring predictors of risk (e.g. the state of the autonomic nervous system) in conscious transgenic mice and test the effect of different anti-arrhythmic interventions in anesthetized mice; 4) analyze the 24−hour Holter ECG recordings in 50 deltaKPQ-LQT3 patients and compare them to those from the transgenic mice.
The expected output is to develop a highly specific and effective therapeutic approach for LQT3 patients and to identify specific patterns associated with life-threatening arrhythmias to improve risk stratification.