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.

doi:10.1101/2025.10.06.680797

bioRxiv · 10.1101/2025.10.06.680797

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.

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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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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. NTBC dosing and outcomes in hereditary tyrosinemia type 1: insights from a representative human model and 99 patients. https://doi.org/10.1101/2025.10.06.680797

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