Development of an innate immune-competent liver spheroid model

Abstract

All nutrients, medications but also toxic substances carried by blood are being delivered to the liver. There they are processed, stored, altered, detoxified, and passed back into the blood or released from the body. Given its role in xenobiotic metabolization, the liver is exposed to a variety of compounds with potentially harmful effects that can result in liver injury. Therefore, it’s impossible to imagine preclinical testing in the drug development process without testing those compounds on appropriate liver models. Drug discovery and development processes are long, incredibly costly, and very inefficient. Attrition rate is spanning from many thousands of new chemical structures to single successful new drug launch, achieved in average after 13 years, with costs estimated to over one billion US dollars. Drug-induced liver injury (DILI) is one major reason for the attrition of candidate drugs during the later stages of drug development. There are two types of DILI―intrinsic DILI which can be predictable and is dose-dependent, and idiosyncratic DILI, which occurs less frequently without obvious dose-dependency and in unpredictable fashion. Mechanisms leading to liver injury are not well described due to a lack of a good experimental model. Sufficient evidence exists that most idiosyncratic cases are mediated by the adaptive immune system, but the triggering factors are unknown. Once the immune response is triggered, it can ultimately lead to cytotoxicity. Therefore, early detection of drug-induced hepatotoxicity is crucial before compounds enter clinical trials. Accurately predicting drug effects on the liver in preclinical research would reduce drug discovery time, cost, and enhance patient safety in the process of drug development.