In vitro implementation of a polygenic risk score for hepatic fat content (PRS-HFC) to unravel interindividual anti-NASH drug responses

Non-alcoholic steatohepatitis (NASH) is a life-threatening liver disease that affects approximately 5% of the population, for which there are no approved pharmacological treatments. Recent findings of the NASH pathogenesis
unveiled that genetic predispositions account for roughly 40% of the cases and that most patients exhibit a disrupted hepatic thyroid signaling. Variants of four genes, namely PNPLA3, TM6SF2, MBOAT7 and GCKR are the most important genetic drivers of NASH.

Here, we aim to investigate if differences in genetic background alter the response to anti-NASH drug candidates and thus call for a better stratification of patients in clinical study setups.

We will use a risk score for hepatic fat content (PRS-HFC) based on the aforementioned genes in cultures of hepatic cells derived from human skin-derived multipotent precursors (hSKP-HPC). HSKP-HPC with different PRS-HFCs will be subjected to NASH-inducing triggers and agonists of the thyroid hormone receptor beta. After mechanistic investigations, poor drug responses in carriers of genetic risk variants will be corrected using specific pharmacological compounds.

This proposal is based on human-specific hepatic models, thereby promoting 3Rs and circumventing the use of animal experimentation and its associated interspecies constraints, and might therefore be pivotal for anti-NASH drug development.