Project: SGK1 inhibition as a novel therapeutic approach in Long QT syndrome

Acronym	SILENCELQTS (Reference Number: EJPRD20-188)
Project Topic	Congenital long-QT syndrome (LQTS) is a rare inherited disorder (prevalence close to 1:2500) 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 iPS-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.
Network	EJP RD
Call	2nd EJP RD Joint Transnational Call for Rare Diseases Research Project (JTC 2020)

Project partner

Number	Name	Role	Country
1	Academic Medical Center	Coordinator	Netherlands
2	University of Milano-Bicocca, San Luca Hospital	Partner	Italy
3	Institute of Physiology	Partner	Switzerland
4	Rappaport Faculty of Medicine and Research Institute	Partner	Israel
5	LQT Therapeutics Inc.	Observer	Canada