Hereditary tyrosinemia type 1 (HT1) is a rare disorder of the tyrosine degradation pathway with unmet therapeutic needs due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme that mainly affects liver cells. NTBC, a potent inhibitor of the key enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), rescues HT1 patients from death, making NTBC indispensable for the patients. However, NTBC-treatment causes tyrosine accumulation in the blood that leads to debilitating side effects. In addition, the risk for hepatocellular carcinoma (HCC) remains high for HT1 patients, even when continuously treated with NTBC. Due to the single gene defect, HT1 qualifies as a target for gene therapy. In the proposed project, we will investigate whether we can improve current gene therapy strategies by developing an NTBC-tolerant variant of HPD (HPDΔntbc) using state-of-the-art protein engineering. As a proof-of-principle we will integrate HPDΔntbc in adeno-associated viral vectors with liver tropism in combination with wild type FAH. This will allow to fully restore the
tyrosine catabolism pathway in transduced hepatocytes and will work without NTBC withdrawal. The efficiency of the treatment will be evaluated in a preclinical FAH-deficient mouse model of HT1. Altogether, we will provide for the first time evidence that protein engineering can be a game changer to advance current treatment options for rare inborn errors of liver metabolism.
Effective start/end date1/01/1931/12/19

    Flemish discipline codes

  • Gastro-enterology and hepatology not elsewhere classified

    Research areas

  • tyrosinemia

ID: 44015158