FFC Impulsion : Gildas Loussouarn (2025-2026)
Gildas Loussouarn is the scientific leader of the Genavie funded project : Innovative mechanism-based therapy for the long QT syndrome through peptide-based activation of hERG and KCNQ1 potassium channels -)
Abstract
Long QT syndrome (LQTS) is a severe genetic arrhythmia disorder characterized by a pathologically prolonged cardiac repolarization, which predisposes patients to ventricular tachyarrhythmias and sudden cardiac death (SCD). Although relatively rare, with a prevalence of 1:2000, it is a leading cause of SCD in the young population. The most frequent types of Long QT syndromes (type 1 and 2) are induced by defective IKr or IKs currents carried by Kv7.1 or Kv11.1 channels, respectively.
We hypothesize that the use of Kv7.1/Kv11.1 activating peptides, which activate the defective channel (Kv7.1 or Kv11.1) through direct interactions with an intracellular domain, will be efficient in restoring normal IKr/IKs current and normal action potential duration (APD) in long QT syndrome, thus opening up a new mechanism-based and more efficient therapeutic approach to prevent arrhythmias than standard therapy.
The main objectives of the project are as follows:
- To optimize our existing potent hERG/KCNQ1-activating peptides to counteract the pathogenic loss-of function variants, thereby normalizing IKr/IKs,
- To investigate the peptides effects on IKr/IKs and APD in WT and LQTS cardiomyocytes carrying different variants to assess variant-specific differences in efficacy,
- To ultimately test peptides efficacy in restoring normal APD in in vivo model.
