PREcision MEDicine with induced pluripotent stem cells for Cardiac Arrhythmias Risk Evaluation

PREMEDiCARE
MSCA iPSCs Long QT Syndrome Precision Medicine

Acknowledgement

This project has been funded by the European Union under the Horizon 2020 Framework Program. Grant Agreement No. 795209.

Research questions that drive this project

Description

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:

  1. demonstrate that the hiPSC technology can reproduce in vitro the clinical disease severity observed in symptomatic vs asymptomatic LQTS mutation carriers;
  2. create an in vitro interdisciplinary pharmacological approach with proarrhythmic drugs which combines matched electrophysiological, contractile, molecular and genetic assays;
  3. 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.

Prova

  1. Sala L.#, Leonov V., Mura M., Giannetti F., Khudiakov A., Moretti A., Crotti L., Gnecchi M. and PJ Schwartz#, Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: the case of hydroxychloroquine in COVID-19, Frontiers in Physiology (2022) # Corresponding Author.
  2. Kozek K., Wada Y., Sala L. et al., Estimating the Post-Test Probability of Long QT Syndrome Diagnosis for Rare KCNH2 Variants, Circulation: Genomic and Precision Medicine (2021)
  3. Lee Y.K. *, Sala L. * et al., MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes Cardiovascular Research (2020) [* equal contribution]
  4. Sala L.* et al., Long QT Syndrome modelling with cardiomyocytes derived from human induced pluripotent stem cells. Arrhythmia & Electrophysiology Review (2019)
  5. Schwartz P.J. and Sala L., Precision vs Traditional Medicine Clinical questions trigger progress in basic science: a favor not always returned. Circulation Research (2019)
  6. Gnecchi M.*, Sala L. *, Schwartz P.J., Precision Medicine and Cardiac Channelopathies: When Dreams Meet Reality. European Heart Journal (2021) [* equal contribution]
  7. Brandão K.O., […], Sala L. et al., Isogenic Sets of hiPSC-CMs Harboring Distinct KCNH2 Mutations Differ Functionally and in Susceptibility to Drug-Induced Arrhythmias. Stem Cell Reports (2020)

Book Chapters

  1. M. Gnecchi, Sala L., P.J. Schwartz, Cardiac Repolarization and Stem Cells: An Emerging Path Toward Precision Medicine. Cardiac Repolarization, N. El-Sherif (ed.), Springer Nature Switzerland AG (2020)