Scalable target identification for metabolic liver disease

Introduction

Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent liver disease that affects up to 6% of the general population and 15-40% of obese persons. MASH is characterized by intracellular triglyceride accumulation (steatosis), chronic inflammation, and hepatocyte injury.

Disease Progression

Importantly, MASH is prone to progress into liver fibrosis, cirrhosis, and hepatocellular carcinoma. Even if diagnosed early, the disease is associated with reductions in life expectancy of 2-4.5 years. Despite tremendous efforts, there are currently no approved pharmacological treatments for MASH.

Associated Conditions

MASH is closely linked to:

• Obesity
• Sarcopenia
• Dyslipidemia
• Insulin resistance

It has become clear that adipose tissue, pancreas, and skeletal muscle produce important signals that orchestrate hepatic metabolism, inflammation, and fibrosis. However, the underlying mechanisms in humans remain poorly understood.

Project Overview

In the 3DMASH project, we will utilize organotypic cultures isolated from patients with a clinical diagnosis of MASH and matched controls to comprehensively map tissue interactions and identify novel targets for pharmacological interventions.

Methodology

By combining co-culture of metabolically relevant tissues from healthy and diseased individuals in microphysiological systems (MPS) with network biology approaches, we will identify novel extrahepatic signaling that positively or negatively influences MASH disease phenotypes.

Screening for Targets

Moreover, we will use the established platform to screen chemogenomic libraries of G protein-coupled receptors, ion channels, and nuclear receptors to identify new pharmacologically accessible targets that activate “healthy” signals or inhibit “disease” cues.

Conclusion

This project thus provides a conceptually novel perspective that considers MASH as a complex pathology caused by dysregulated tissue interactions and targets these disease mechanisms, which are neglected by current drug development programs, to finally develop effective treatments.