SGK1 inhibition as a novel therapeutic approach in Long QT syndrome
In this project FRRB funds Partner number 1:
- Istituto Auxologico Italiano IRCCS, Principal Investigator Dr. Lia Crotti.
|Pathology of interest:
|Area of research:
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|| € 476.600,00
- Amsterdam University Medical Center - Leading partner, Netherlands
- University of Bern (UNERN), Switzerland
- Technion - Israel Institute of Technology, Israel
Congenital long-QT syndrome (LQTS) is a rare inherited disorder (prevalence approximately1:2500) associated with life-threatening arrhythmias and sudden cardiac death (SCD) in relatively young and otherwise healthy individuals.
LQTS has a heterogeneous genetic basis, with various LQTS subtypes caused by mutations in distinct genes related to cardiac ion channel function.
Current symptom-directed therapies aimed at reducing arrhythmia triggering events, including lifestyle changes, beta blockade, and left cardiac sympathetic denervation, only partly prevent arrhythmic events, and SCD still occurs in a substantial number of LQTS patients.
Within SILENCE-LQTS, we will investigate a novel, mechanism-targeted therapy, comprising pharmacological inhibition of the serum and glucocorticoid regulated kinase-1 (SGK1).
In contrast to current symptom-directed therapies, this novel approach is designed to correct the pro-arrhythmic alterations in sodium homeostasis caused (in)directly by the underlying genetic defect. Efficacy of a SGK1 inhibitor, developed by our industry partner, will be systematically tested in vivo and on the cardiomyocyte and whole heart level in well-established unique transgenic rabbit and mouse models of different LQTS subtypes.
Furthermore, its efficacy will be tested in human iPSC-derived cardiomyocytes (hiPSC-CMs) obtained from LQTS patients and in 2D/3D engineered hiPSC-CM tissues.
These pre-clinical studies will establish the anti-arrhythmic potential of SGK1 inhibition, paving the way for future clinical application aimed at preventing SCD in LQTS.