Liver diseases such as nonalcoholic steatohepatitis (NASH) represent major medical needs and, by extension, opportunities for drug developers. However, efforts to develop drugs to treat NASH and other forms of steatohepatitis have been hindered by the limitations of animal models, which are an imperfect stand-in for the human liver.
Recent advances in human stem cell culture have raised hopes that researchers can create miniature versions of human livers, known as organoids, that provide a more accurate picture of the effects of medicines in humans.
Writing in the journal Cell, researchers from Tokyo Medical and Dental University and Cincinnati Children's Hospital Medical Center recently shared details of their efforts to advance that idea.
The paper describes efforts to move beyond early models, which primarily differentiated cells into hepatic epithelial cell types, and create organoids more representative of the mix of pro-fibrotic and inflammatory cell types found in the human liver.
Those efforts led to the creation of organoids that develop steatohepatitis in a manner comparable to the human liver.
The researchers wrote, “These multi-cellular human liver organoids coupled with free fatty acid treatment recapitulate the progressive, stepwise nature of steatohepatitis-like pathology including steatosis, inflammation and fibrosis.”
Extensive fibrosis of the organoids led to stiffness. That feature is significant given the important role liver stiffness now plays in the assessment of how to treat NASH patients, leading the researchers to talk up the prospect of using the organoids for drug screening.
The project generated evidence that the organoids can serve as a model for the efficacy of drugs. The researchers developed one of the sets of organoids using cells from someone with Wolman disease, enabling them to assess the efficacy of Intercept Pharmaceuticals’ Ocaliva in the indication.
According to the researchers, “[Human liver organoids] derived from patients with genetic lysosomal enzyme deficiency lead to an exaggerated steatohepatitis phenotype as seen in patients, followed by in vitro rescue with a clinically active compound via FXR agonism.”
Survival of the Wolman organoids was “significantly improved” by exposure to the drug and lipid accumulation was suppressed. In contrast, magnesium supplementation had no effect, as has been the case when the treatment is tested in clinical trials.
