Researchers from the Organoid group (formerly known as Clevers group, Hubrecht Institute) together with researchers from the Princess Máxima Center for Pediatric Oncology have developed novel human organoid models of fatty liver disease. Their models will aid in testing and developing novel medicines to treat fatty liver disease.
They used these models to shed light on drug responses and established a CRISPR-screening platform to identify novel disease mediators and potential therapeutic targets. These models will aid in testing and developing novel medicines to treat fatty liver disease and help to get a better understanding of the disease biology.
Their study is published in Nature Biotechnology in an article titled, “Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis.”
“The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening,” wrote the researchers. “Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M), and monogenic lipid disorders (APOB and MTTP mutations).”
The researchers turned to organoids to establish three models that capture different triggers of fatty liver development. They first “fed” the organoids with a mixture of fatty acids to mimic a Western diet. As a second model, the team introduced the top risk mutation for fatty liver disease into their organoid system using prime editing. In the third model, the researchers modeled genetic lipid disorders using CRISPR-Cas9 to investigate how these disorders influence the development of fatty liver disease.
The team then screened a large number of drug candidates to treat fatty liver disease on the newly developed organoid models. Interestingly, the researchers observed that the different fatty liver organoid models responded to the drugs in a very comparable manner. This allowed them to identify a subset of drugs that were effective across all models.
The researchers went on to use their organoid models to establish a genetic screening platform to identify novel genes with roles in fatty liver disease. The researchers turned their organoids into a CRISPR-screening platform, named FatTracer.
These novel fatty liver organoid models pave the way for many future directions.