A novel NASH model for target and drug candidate identification

Introduction

NASH is the progressive form of NAFLD that underlies the development of fibrosis, cirrhosis, and hepatocellular carcinoma. The global prevalence of NASH is estimated at 1 billion individuals. NASH is a major cause of death, now the major reason for liver transplantations, and the disease is an important cause of hepatocellular cancer (HCC). Currently, there are no FDA-approved drug therapies available.

Hepaspher Project

Within the ERC project Hepaspher, a new liver model was developed in which human hepatocytes and non-parenchymal cells are grown in a 3D spheroid structure. This structure phenotypically closely resembles human liver in vivo with respect to transcriptome, proteome, and metabolome for up to 35 days.

Applications of the Hepaspher Model

This model has proven to be of valuable use for the development and treatment of liver diseases such as:

• Steatosis
• Cholestasis
• Hepatitis
• Insulin resistance
• Fibrosis

SPHERO-NASH Project

In the SPHERO-NASH project, we focus on a more complex system whereby both inducers and mechanisms of NASH formation are studied. This includes:

1. Drug-induced inhibition of NASH
2. Studies of extracellular matrix (ECM) degradation, including collagens
3. The role of ECM degradation control in the development and treatment of NASH

Research Methodology

For this purpose, HTS-based screening in the SPHERO-NASH spheroid system will take place, utilizing both:

• siRNA target libraries
• Chemical inhibition libraries at HepaPredict AB

The proposed delivery of novel compounds/targets can be further processed in drug developmental projects.

Commercialization Strategy

We propose to commercialize the SPHERO-NASH model itself, as well as targets and compounds found by siRNA and compound screening that regulate NASH formation and degradation.

Knowledge Transfer

We aim to assess and demonstrate the commercial value to the pharmaceutical industry by building a strong knowledge transfer strategy. The SPHERO-NASH model thus has great fundamental and commercial potential in NASH drug discovery and development.