James Sidaway, AZ
Written by Jackie Howard Tuesday, 08 May 2012 11:02
High content analysis for detection of drug induced structural cardiotoxicity
Cardiotoxicity is a major cause of drug withdrawal from the market and of attrition during drug development. Drug induced cardiotoxicity results from both functional effects and structural changes to the heart. In vitro screens to identify subtypes of functional cardiotoxicity in new drug candidates are widely used in the pharmaceutical industry (e.g. cardiac ion channel screening for arrhythmias). In contrast, screens for drugs that cause structural cardiotoxicity have not been developed due to poorly defined mechanisms and inadequate in vitro models. Recent advances in stem cell technologies now provide physiologically relevant, homogenous and reproducible cardiomyocyte cell systems that are amenable to high throughput assay development. High content analysis (HCA) by automated live cell microscopy uses fluorescent dyes to detect changes in organelle function and levels of critical cellular molecules. Compared to conventional cytotoxicity assays HCA is potentially able to detect a greater range of toxic mechanisms at sub-cytotoxic drug concentrations. This presentation will describe the development of a combined cytotoxicity and HCA screen in human embryonic stem cell derived cardiomyocytes that measures intracellular calcium level and endpoints of mitochondria and endoplasmic reticulum homeostasis to detect structural cardiotoxic liabilities in candidate drugs. The relative sensitivity of conventional cytotoxicity measurement and HCA in relation to clinical drug exposure and the value of each endpoint at giving insight into potential mechanisms of cardiotoxicity will also be presented.
AstraZeneca, Innovative Medicines