Characterisation of Biomarkers for Non-Alcoholic Steatohepatitis

Characterisation of Clinical Biomarkers That Predict Lesions, and Lesion Progression and Regression in Established Rodent Models of Non-Alcoholic Steatohepatitis (NASH)

There is a tremendous unmet medical need for therapies that prevent and treat liver-related morbidity that is associated with the severe stages of non-alcoholic fatty liver disease (NAFLD): non-alcoholic steatohepatitis (NASH) and liver fibrosis. However, development of such therapies is impeded by a lack of well-validated translational biomarkers that can assess disease progression and response to therapy in patients as well as in animals. This project aimed to evaluate and validate emerging clinical biomarkers in established animal models of NASH to facilitate translational research and accelerate drug development.

NAFLD has become the most common cause of chronic liver disease in Western countries, and its prevalence continues to rise in parallel with increasing rates of obesity and type 2 diabetes, to which it is strongly related. NASH, the progressive form of NAFLD, is a serious liver disease that can further progress to cirrhosis and liver cancer. There is currently no approved pharmacological therapy for NAFLD/NASH.

In this project, we first characterised changes in a panel of candidate biomarkers at different stages of lesion development, in 2 established mouse models for NASH. Next, we assessed the power of biomarkers selected in the first phase of the project to predict changes in disease status after drug treatment. Candidate biomarkers were selected based on published associations from clinical studies. We found that most of the measured biomarkers showed a characteristic time profile and differed between diseased animals and healthy controls (similar to what is observed in patients) but only a small subset showed a meaningful link with the degree of disease development. Hepatic fibrosis (a feature of advanced disease) could be predicted accurately by combining two biomarkers in an algorithm. This algorithm was also found to reflect the response to drug treatment, which means it may be of value to monitor responsiveness to pharmacological therapy.

Summary

Development of new therapies for non-alcoholic steatohepatitis (NASH) is impeded by a lack of well-validated translational biomarkers that can assess disease progression and response to therapy in patients as well as in animals. In this project we characterised emerging clinical biomarkers in established animal models of NASH to facilitate translational research and accelerate drug development.

Technology Readiness Level (TRL)

3-5

Time period

2 years

Partners