This Small Business Innovation Research (SBIR) Phase II project is aimed towards development of a human micro-liver platform and assay technologies for cost-effective, high-throughput, and quantitative screening of drug-induced liver injury (DILI) and drug-drug interactions (DDI) following chronic exposure to pharmaceuticals. While primary human hepatocytes isolated from the liver are widely utilized in the pharmaceutical industry for drug screening, these cells rapidly (hours) lose phenotypic functions under conventional culture conditions. Recently, a human liver tissue model with defined microscale architecture has been developed that maintains phenotypic functions of primary hepatocytes for several weeks in vitro (micro-livers). This project proposes to develop assay technologies (gene expression, reporter-based, and high content imaging) with micro-livers in a high-throughput multi-well format for DILI and DDI screening in early drug discovery.
The broader impacts of this research are novel approaches for the development of high-throughput, physiologically-relevant platforms for assessing the potential of compounds to cause adverse effects on organs. The liver platforms developed here may enable the elimination of drugs with problematic toxicity profiles much earlier in the drug development pipeline towards substantially reducing the cost to develop a successful drug ($1 billon per drug), increasing the likelihood of clinical success, and limiting human exposure to unsafe drugs. In the future, these platforms may be useful for evaluating the injury potential of environmental toxicants, in fundamental investigations of liver physiology and disease, and for personalized medicine.
