Multiplexed high-content assay for toxicity profiling using live iPSC-derived cardiomyocyte lines with lineage-specific barcoding

Project Summary Abstract Human induced pluripotent stem cellshiPSCsare poised to transform toxicological evaluationhowever new approaches to enable their functional and structural profiling are needed to improve the utility of hiPSCbased models for predictive and mechanistic toxicology screeningThis need is addressed by our project s Specific Aims that encompassdevelopment of a novel platform for generation of hiPSC derived reporter cellsgeneration of a panel of multicolor hiPSC derived cardiomyocyteshiPSC CMswith stable lineage specific fluorescent reportersandimplementation and validation of a pilot machine learning enabled predictive cardiotoxicity screen using these toolsThe proposed tools are configured to be extensible to other toxicologyrelevant pathways and phenotypes making it uniquely positioned to capitalize on the growing commercial need for high throughput predictive toxicology assaysThe project deliverables benefit public health by improving the ability to rapidly identify liabilities in specific cardiomyocyte lineage typesthus reducing the time and cost to pinpoint cardiotoxicity of pharmaceutical and environmental chemicals Project Narrative The assay and reagents established in the course of this project directly address the goals of significant initiatives to improve the effectiveness of cardiotoxicity testingsuch as the FDA s CiPA initiative and the work of the Cardiac Safety Research ConsortiumThe resulting improvements in the pace and precision of drug testing will result in public health benefit through the development of more cost effective and safer medicinesBeyond toxicological evaluation of therapeutic compoundsour innovative technology will deliver additional benefit to public health by virtue of its utility in investigating the toxicities of environmental chemicalsin line with the focus of government agencies and initiatives such as the EPA and Toxin the US and EU ToxRisk in Europe