Non-alcoholic fatty liver disease (NAFLD) models in drug discovery

ABSTRACT

Introduction: The progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is a rapidly emerging public health crisis with no approved therapy. The diversity of various therapies under development highlights the lack of consensus around the most effective target, underscoring the need for better translatable preclinical models to study the complex progressive disease and effective therapies.

Areas covered: This article reviews published literature of various mouse models of NASH used in preclinical studies, as well as complex organotypic in vitro and ex vivo liver models being developed. It discusses translational challenges associated with both kinds of models, and describes some of the studies that validate their application in NAFLD.

Expert opinion: Animal models offer advantages of understanding drug distribution and effects in a whole body context, but are limited by important species differences. Human organotypic in vitro and ex vivo models with physiological relevance and translatability need to be used in a tiered manner with simpler screens. Leveraging newer technologies, like metabolomics, proteomics, and transcriptomics, and the future development of validated disease biomarkers will allow us to fully utilize the value of these models to understand disease and evaluate novel drugs in isolation or combination.

KEYWORDS:

• Non-alcoholic fatty liver disease (NAFLD)
• non-alcoholic steatohepatitis (NASH)
• organotypic
• preclinical
• steatosis
• inflammation
• fibrosis
• hepatocyte
• hepatic stellate cell

Article highlights

• The lack of approved therapies for non-alcoholic fatty liver disease (NAFLD) fuels fervent drug discovery and development efforts in the field.

• The diversity of disease mechanisms and pathways underscores the need for robust models for successful target identification, validation and assessment of therapies.

• Animal models use genetic, dietary or chemical approaches to recreate progressive disease changes allowing assessment of systemic drug responses, but have translational limitations due to species differences.

• Advanced human in vitro systems designed to restore physiological relevance and responsiveness and recreate disease biology are a complimentary approach to address these limitations.

• The choice of models, alone or in combination can vary depending on the application, and benefit from harnessing the technological advances in endpoint measurements, data analytics and disease centric approaches.

This box summarizes key points contained in the article.

Declaration of Interest

B Cole, R Feaver and B Wamhoff are all employees and have stock in HemoShear Therapeutics while A Dash holds stock with them also. A Dash is an employee of Genentech Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The research described was funded in part by SBIR grants 2R44DK100136 and 4R44DK104456-02 to Hemoshear Therapeutics.