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Predictive cardiotoxicity testing based on human stem cell-derived cardiomyocytes

Project

Food and consumer protection

This project contributes to the research aim 'Food and consumer protection'. Which funding institutions are active for this aim? What are the sub-aims? Take a look:
Food and consumer protection


Project code: BfR-ZEBET-08-1328-539
Contract period: 01.11.2015 - 30.04.2017
Purpose of research: Applied research

The aim of this project was to devise an efficient methodological workflow for monitoring cardiotoxic side-effects of drugs using a human cellular model as an alternative to animal trials: Focussing on pro-arrhythmic effects of candidate compounds, human pluripotent stem cells (hPSCs) were to be differentiated into cardiomyocytes and be analyzed on multielectrode arrays, to subsequently serve as model system for reliably detecting cardiotoxic effects of drugs in routine operations. This workflow was to be established using existing as well as yet-to-be established disease models of known genetically inherited cardiac channelopathies.

Both projects have been highly successful and got published by the end of the funding period. I have attached both these papers as supplementary information accompanying this report: M. Marczenke, I. Piccini, I. Mengarelli, J. Fell, A. Röpke, G. Seebohm, A.O. Verkerk*, B. Greber*, Cardiac Subtype-Specific Modelling of Kv1.5 Ion Channel Deficiency Using Human Pluripotent Stem Cells, Frontiers in Physiology, 8 (2017) 469. Key results: Thanks to developing our methodology by means of this research grant, we could - for the first time - show in an hPSC model of LQT3 spontaneous so-called early afterdepolarizations (EADs) which are triggers of arryhthmia in patients. Treating the cells with drug that has successfully been used in the underlying patient fully suppressed EADs in our model. D. Malan, M. Zhang, B. Stallmeyer, J. Müller, B.K. Fleischmann, E. Schulze-Bahr, P. Sasse*, B. Greber*, Human iPS cell model of type 3 long QT syndrome recapitulates drug-based phenotype correction, Basic Res Cardiol, 111 (2016) 14. Key results: Our revised methodology allowed us to convincingly model a specific variant of genetically inherited atrial fibrillation in a cardiac subtype-specific manner. Different drugs were then successfully used to promote more arrhythmia-like phenotypes, which nicely exemplified the power of this model system for the more sensitive detection of cardiotoxic effects.

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Subjects

Framework programme

BMEL Frameworkprogramme 2008

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