Preclinical model systems are invaluable tools for drug discovery and development. But many complex diseases, such as nonalcoholic steatohepatitis (NASH), are difficult to recapitulate in the laboratory. NASH is a progressive metabolic disease that takes years, if not decades, to develop in humans. Successfully modeling all the key physiological events (from steatosis to inflammation and fibrosis) evident in clinical NASH has been extremely challenging in both in vivo animal models and in vitro cell-based models.
Conventional in vitro models, such as human hepatocytes cultured in 2D, offer a fast, efficient means to assess certain characteristics of NASH with compound testing (for example, the compound’s EC50), but they lack other cell types involved in the disease’s progression and are often suitable only for short-term assays. More advanced tissue-specific, human 3D co-culture systems, such as InSphero’s 3D InSight™ Human Liver Microtissues, are more appropriate for evaluating compound mechanisms of action in long-term experiments, but they, too, are limited in their ability to mimic NASH progression.
So…how do you choose the most suitable model at each stage of drug development?
One of the first things we do when we meet with a new NASH discovery partner with a promising lead candidate or a long list of potential combination therapies is to develop a detailed experimental program. Together, we discuss what type of information is needed to answer the pathophysiological and mechanistic questions at hand. We can then make informed decisions about which models, assays, and endpoints are best suited to answer those questions. We've found that it often helps to organize this information into a simple checklist that we can use as we map out a strategy for rigorously testing monotherapies and combination therapies in vitro.
If you'd like to know more, I encourage you to:
Both Eva and I would love to hear your thoughts and welcome any suggestions for future topics you'd like us to cover in our blogs or upcoming webinars. Please use the comments section below to share your ideas!
Watch this video to learn how we applied our scalable Akura™ technology and 10 years of experience in perfecting 3D in vitro human liver models to develop the first automation-compatible 3D in vitro human liver disease platform for NAFLD and NASH. And read about how pharma companies are applying this platform in their drug discovery programs.
Cover image: High content imaging of this 3D multicellular human liver model shows the changes in model phenotype under healthy control conditions (A) and after NASH induction with a specialized media that contains higher sugar levels and free fatty acids (lipids). Treatment with low (C) and high (D) concentrations of an anti-steatotic clinical drug candidate leads to a decrease in intracellular lipids. Nile Red staining (magenta) captures a normal amount of lipids (green) in the control and after treatment with high drug concentrations of the drug, whereas steatotic hepatocytes are abnormally enlarged and filled with lipid vacuoles. Hoechst staining for nuclei (blue) further highlights macrovesicular steatosis (engorgement of hepatocytes by lipids that displace nuclei), mimicking the fatty liver disease state in humans. (Photo credit: InSphero AG, imaged on a Yokogawa high-content screening system.)