An In Vitro Pre-Clinical MPS Model for Metabolic Associated Steatohepatitis for Drug Efficacy

NAFLD (non-alcoholic fatty liver disease) is a global epidemic that affects 25% of the world’s population, with its epicentre in the West. Twenty percent of NAFLD patients go on to develop the most severe form of the disease, NASH (metabolic-associated steatohepatitis) which is characterized by lipid accumulation, infiltration of immune cells, and liver fibrosis. While NASH is well-characterized, there is currently no therapeutic cure for these diseases. One of the main reasons preclinical models for testing efficacy fail to adequately predict clinical outcomes is that current preclinical models mostly comprise animal models that fail to recreate the full spectrum of the disease and often lead to poor translation to humans. There is an urgent need to improve current preclinical NASH models to better predict drug efficacy. Microphysiological systems (MPS), also known as organ-on-a-chip (OOC), have been developed as a new alternative method (NAM) to bridge the gap between preclinical predictions and clinical outcomes. MPS models of the liver can capture the complexity of the liver’s microenvironment and express a wide range of human-relevant translational biomarkers. In this NASH MPS model, multiple primary cells (hepatocytes, hepatic stellate cells, and Kupffer cells) are co-cultured on a perfused scaffold to form a 3D microtissue. Exposure of this microtissue to fatty media generates a clinical-like NASH phenotype, making this model a good fit for drug efficacy testing. Here, we show the model’s potential to assess the efficacy of four anti-NASH compounds, currently in late-stage clinical trials, using a panel of inflammatory, fibrotic, and steatosis biomarkers. We also discuss its ability to investigate the mechanism of drug action.

Learning Objectives: 

1. Identify preclinical drug development challenges for NASH studies.

2. Introduce a liver MPS model for investigating NASH.

3. Demonstrate how this NASH liver MPS provide translatable insights into drug efficacy for NASH therapeutics.