An ongoing challenge in NASH Drug Discovery is selecting "fit for purpose" models for preclinical drug screening. InSphero liver expert Sue Grepper and Head of Liver Solutions Eva Thoma recently wrote a GEN tutorial on this topic to help NASH researchers choose the right experimental design considerations for NASH drug screening while testing for promising lead candidates and combination therapies before advancing to clinical trials. Here's what they recommend.
Choosing the right model system for NASH drug discovery
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 NASH drug development?
A checklist for data-driven experimental design in NASH drug discovery
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:
- Read our tutorial in Genetic Engineering and Biotechnology News. We take a closer look at experimental design considerations for selecting the most appropriate models for different types of experiments at various stages in the drug development pipeline, using an antisteatotic drug candidate as an example.
- Register for my webinar on Redefining NASH Discovery: A New Approach to Complex Disease Modeling. I'll show you how quickly and efficiently you can screen compounds and combination therapies using an in vitro platform -- 6x faster than mouse models -- that reflects the full disease progression in humans-- from fat accumulation in hepatocytes to inflammation and fibrosis of liver tissue. You'll also get a preview of RNASeq data that confirms the induction of the NASH phenotype in our model.
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!
Discover what you can do with 3D InSight™
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.)