Human induced pluripotent stem cells (hiPSCs) are poised to transform toxicological evaluation, however new approaches to enable their functional and structural profiling are needed to improve the utility of hiPSC -based models for predictive and mechanistic toxicology screening. This need is addressed by our project?s Specific Aims that encompass (1) development of a novel platform for generation of hiPSC-derived reporter cells; (2) generation of a panel of multicolor hiPSC-derived cardiomyocytes (hiPSC-CMs) with stable lineage specific fluorescent reporters; and (3) implementation and validation of a pilot machine learning-enabled predictive cardiotoxicity screen using these tools. The proposed tools are configured to be extensible to other toxicology- relevant pathways and phenotypes making it uniquely positioned to capitalize on the growing commercial need for high-throughput predictive toxicology assays. The project deliverables benefit public health by improving the ability to rapidly identify liabilities in specific cardiomyocyte lineage types, thus reducing the time and cost to pinpoint cardiotoxicity of pharmaceutical and environmental chemicals.
The assay and reagents established in the course of this project directly address the goals of significant initiatives to improve the effectiveness of cardiotoxicity testing, such as the FDA?s CiPA initiative and the work of the Cardiac Safety Research Consortium. The 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 medicines. Beyond toxicological evaluation of therapeutic compounds, our innovative technology will deliver additional benefit to public health by virtue of its utility in investigating the toxicities of environmental chemicals, in line with the focus of government agencies and initiatives such as the EPA and Tox21 in the US and EU-ToxRisk in Europe.
