Abstract

Developing Complex Cellular Models to Increase Phenotype and Disease Relevance in Drug Discovery

Christopher Schofield, Group Leader/Investigator, GlaxoSmithKline

Hepatotoxicity is the most frequently cited reason for drug withdrawal from the market and is a leading cause of attrition in drug discovery and development. By increasing the phenotypic relevance of in vitro hepatotoxicity assays we aim to elevate the position of complex cellular models up the drug screening cascade to improve patient safety, reduce drug attrition and reduce animal usage. Two strategies to address this are Precision Cut Tissue Slices (PCTS)* and 3D primary human hepatocyte spheroid cultures*. PCTS potentially represent one of the best phenotypically and structurally relevant in vitro 3D models. Culture methods were established that extended the viable and functional life span of outer cell layers from a few hours up to 5 days. However, an autolytic core developed within the slices but a concentration response effect was as measured following exposure to some hepatotoxins. In recent years it has become clear that moving cultured cells from 2D monolayers into 3D systems influences their biological relevance and response. Culturing primary human hepatocyte cells in 3D spheroids enabled chronic exposure to known tool hepatotoxic compounds and demonstrated improved predictivity over other 2D models and PCTS. Our learning’s and data will be presented comparing these systems to current in vitro models along with how they might be used in various areas of the drug discovery and development continuum. *The human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents. All animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals.