NaV1.5 regulation fine-tuning as a therapy for cardiac Conduction and Arrhythmic diseases at Risk of suddEn Death

Introduction

The voltage-gated sodium channel (Na-channel; NaV1.5) is a central component of cardiac electrogenesis. Its dysfunction can lead to ventricular fibrillation and sudden cardiac death. While NaV1.5 represents a highly relevant therapeutic target for the prevention of life-threatening cardiac arrhythmias, therapies that target the expression or function of this channel are non-existent.

Importance of Therapy

Such a therapy would provide, for the first time, an alternative for the invasive and costly cardioverter defibrillator or pacemaker therapies currently used. The NaV1.5-CARED consortium proposes to capitalize on their largest worldwide cohorts of patients with inherited cardiac electrical and conduction defects to uncover regulatory regions and proteins that modulate NaV1.5 expression and function with the goal to develop and validate innovative therapies to restore the function of NaV1.5.

Objectives

We have three objectives:

1. Predict the risk of (fatal) arrhythmia and conduction defect at the individual level by developing a personalized polygenic risk score (PRS).
2. Characterize the molecular mechanism associating regulatory DNA regions and genes with the cardiac diseases to uncover new therapeutic targets.
3. Develop new candidates for therapeutic intervention able to restore NaV1.5 loss of function.

Methodology

After databases harmonization, we will conduct whole genome genetic studies to identify variants associated with ventricular arrhythmia and conduction defects and generate PRS relevant to stratify the risk of arrhythmia and degree of conduction defect.

Future Directions

Genetic studies will also be used to identify new therapeutics that will be evaluated in dedicated and high-throughput human cardiomyocytes derived from induced pluripotent cell models.