PREMEDiCARE · PREcision MEDicine with induced pluripotent stem cells for Cardiac Arrhythmias Risk Evaluation
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-10-01 → 2021-07-03
- EU contribution
- €168,277
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
PREcision MEDicine with induced pluripotent stem cells for Cardiac Arrhythmias Risk Evaluation
The Long QT Syndrome (LQTS) is one the most common inherited cardiac arrhythmias, representing one of the leading causes of sudden cardiac death below age 20. LQTS is clinically visible as a pathological prolongation of the QT interval on the electrocardiogram as a consequence of genetic variants in genes encoding for cardiac ion channels or other key cardiac proteins, or of exogenous factors such as medications. The in vitro study of LQTS and congenital cardiac arrhythmias has profoundly changed in the last 10 years. Earlier, aspects of LQTS could be partially reproduced in vitro only in heterologous systems (i.e. by introducing the mutated ion channel of choice into cancer cell lines), by pharmacologically simulating the effect of QT-prolonging drugs in animal cardiomyocytes (CMs) or by using costly and complex transgenic animal models. None of these experimental models is capable of fully reproducing the clinical condition of LQTS patients. Better, more refined and more ethical experimental models to investigate the underlying mechanisms of LQTS and congenital cardiac arrhythmias are needed. Human induced pluripotent stem cells (hiPSCs) have demonstrated to be a very powerful tool to recreate the clinical condition of a patient in vitro, and this has revealed valid also for LQTS and cardiac arrhythmias; hiPSCs guarantee a virtually unlimited source of human CMs which can be used to identify the molecular mechanisms of a disease and to test drugs on cells directly derived from a patient (i.e. sharing the same diseased genetic background). However, despite the proven capability of CMs derived from hiPSCs (hiPSC-CMs) to reproduce simple clinical hallmarks of LQTS variants in vitro (e.g. QT prolongation), we do not know how they behave in modelling complex features of LQTS; one aspect poorly investigated in vitro was the incomplete penetrance, the fact that individuals carrying a specific disease-causing variant may exhibit life-threatening symptoms while others, still affected by the same variant, are completely asymptomatic. Logically, this complicates the diagnosis, the risk stratification and the therapy for LQTS patients. The PREMEDiCARE project has two main goals: 1) Demonstrate that hiPSC-CMs can reproduce the clinical severity observed in symptomatic vs asymptomatic carriers of variants associated with LQTS. 2) Identify and functionally characterize factors correlated with an altered risk of drug-induced LQTS in symptomatic vs asymptomatic LQTS patients. These aims are challenging but important for society and for the whole scientific community as they will contribute to refine human-based experimental models that can represent reliable alternatives to animal testing and help to develop precision medicine approaches for the prevention and/or treatment of congenital and acquired cardiac arrhythmias such as LQTS.
Data: CORDIS, © European Union
Project objective
Long QT Syndrome (LQTS) is a severe arrhythmogenic condition characterised by the prolongation of the QT interval on the electrocardiogram. It is caused by genetic factors (congenital) or drugs (acquired) and sudden cardiac death can be the first manifestations of the disease. Advancements in genetic screenings have revealed profound links between genotype and phenotype for LQTS, improving diagnosis, risk stratification and therapy; However, it is still poorly understood why patients with identical pathogenic mutations have different clinical phenotypes, which factors are involved in this unpredictable disease severity and how we can protect these subjects from drug treatments that are safe in the general population.We do need improved and more physiological in vitro models to simulate arrhythmias in vitro, effective for drug testing, to identify, evaluate and study factors that shape the arrhythmogenic risk in vulnerable subjects.Here I propose a precision medicine approach that uses human pluripotent stem cells-derived cardiomyocytes (hPSC-CMs) from LQTS families (rare resources that include male, female, symptomatic and asymptomatic patients) to: i) demonstrate that the hiPSC technology can reproduce in vitro the clinical disease severity observed in symptomatic vs asymptomatic LQTS mutation carriers; ii) create an in vitro interdisciplinary pharmacological approach with proarrhythmic drugs which combines matched electrophysiological, contractile, molecular and genetic assays; iii) identify and evaluate the factors affecting the arrhythmogenic risk in predisposed subjects.This pipeline to assess arrhythmia susceptibility from patient-specific hiPSC-CMs can be applicable to other arrhythmogenic syndromes. The results of this project will contribute to reduce the use of animal models in preclinical research, to create safer, more effective drugs for humans and to promote the shift of new therapeutic approaches towards precision or personalised medicine.
Original text from CORDIS.
Participants
- ISTITUTO AUXOLOGICO ITALIANO · MILANOCoordinatorItaly
Links
Data: CORDIS, © European Union