In this webinar, Dr. Jonathan Sexton presents an evaluation of iPSC-derived human liver organoids (HLOs) that spontaneously produce autologous hepatocytes, stellate, and Kupffer cells for drug-induced liver injury (DILI) risk prediction. The study leveraged Emulate Organ-Chips while using a multi-omics approach that integrated metabolomics, single-cell RNA sequencing, and high-content imaging to predict DILI risk with imputation of the mechanism of action. HLOs on the Liver-Chip were shown to dramatically increase albumin production and CYP450 expression while releasing ALT/AST when treated with drugs known to cause DILI at clinically relevant concentrations. Furthermore, HLO Liver-Chips were able to be used to evaluate inarigivir for hepatitis B by predicting the hepatotoxicity of the tenofovir-inarigivir combination that was responsible for unanticipated liver injury and death in a phase-III clinical study. This combination caused steatosis and mitochondrial perturbation in HLOs that recapitulate the clinical and histological presentation of the liver injury with a mechanism similar to fialuradine.
The study “A Multi-Omics Human Liver Organoid Screening Platform for DILI Risk Prediction” is available to read on bioRxiv.