Bosma P.J.: Novel therapies for liver disease

Project Details


Adeno Associated Virus (AAV) mediated liver directed gene therapy for inherited unconjugated hyperbilirubinemia in Crigler-Najjar syndrome type-1(CNS-1) , a model for inherited metabolic liver disorders.

Gene therapy

Unconjugated hyperbilirubinemia in CNS-1 is caused by deficiency for UGT1A1, a liver enzyme that catalyses the conjugation of bilirubin, an essential step for efficient biliary excretion. To investigate if gene therapy is a feasible treatment option, we injected 5 x10e12 gc/kg of rAAV encoding the human UGT1A1 gene into the portal vein of the relevant animal model for CN syndrome, the Gunn rat. A single injection proved sufficient for life-long correction of serum bilirubin levels. In addition we showed that immune responses towards the human UGT1A1 protein were prevented by restricting its expression to the hepatocytes using a liver specific promoter. In collaboration with GENETHON a novel vector has been developed that provides therapeutic efficiency with a dose shown to be safe. The GMP production of this vector is ongoing and upon the tox studies in 2015 and in the start of 2016, a phase 1 trial is planned for the end of 2016 beginning 2017. Screening of CN patients that are intereted for this upcoming trial has started and will allow efficient inclusion of patient in this trial. In addition to CN other gene therapy for other inherited liver disorders like PFIC is developed.

Liver function and bile transport.

In vivo knock-down using AAV mediated expression of Sh constructs is used to reduce the expression of liver speicfic transporters to clarify their role in liver function and especially in bile formation. Efficient knock down of for instance P4 type ATPases is used to clarify their role in biliary transport.

Themes: Gastro-intestinal diseases and Metabolic Disorders
Effective start/end date1/02/2007 → …