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

Pham, Q. T.; Tamnanloo, F.; M'Callum, M.-A.; Beaulieu, E.; Mghabghab, R.; Theoret, Y.; Mitchell, G.; the Quebec NTBC Study Group, ; Cyr, D.; Waters, P. J.; Doyon, Y.; Halac, U.; Raggi, C.; Paganelli, M.

2025-10-07 genetics
10.1101/2025.10.06.680797 bioRxiv
Show 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.

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