NTBC dosing and outcomes in hereditary tyrosinemia type 1: insights from a representative human model and 99 patients

Abstract

Hereditary tyrosinemia type 1 (HT1) is a rare and severe metabolic liver disorder caused by fumarylacetoacetate hydrolase (FAH) deficiency. The optimal dose and long-term effects of the only available treatment, nitisinone (NTBC), remain unclear due to the absence of clinical trial data. Here, we generated a representative human in vitro model of HT1 using iPSC-derived hepatocytes, which faithfully recapitulated key disease features. We investigated the mechanisms of FAH deficiency-induced hepatocellular injury and evaluated the effects of NTBC treatment. We confirmed treatment efficacy and identified 50 {micro}mol/L as the minimal effective NTBC concentration to prevent cellular damage. This protective dose was subsequently validated in a large cohort of 99 HT1 patients, providing compelling evidence for establishing minimal therapeutic NTBC levels. Notably, approximately 10% of disease-associated genes, many implicated in hepatocellular carcinoma, remained dysregulated despite treatment, raising concerns that NTBC may not fully eliminate long-term oncogenic risk.