Gene Therapy Research Unit

A joint initiative of The Children's Hospital at Westmead and Children's Medical Research Institute

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Liver-Targeted Gene Therapy J. Curtin, A. Dane and I. Alexander Many genetic diseases, affecting proteins and enzymes made in the liver, may be cured or ameliorated by liver-directed gene therapy. For such therapy to be successful, it is necessary for the normal copy of the gene to be functional in a sufficiently high number of liver cells called hepatocytes. Despite extensive research into improving and developing means to deliver genes to hepatocytes, it is difficult to modify sufficient hepatocytes to achieve a therapeutic effect with the currently available methods. One way to overcome the limitations of the current methods to deliver genes to the liver is to expand the population of hepatocytes to which the gene has been delivered in a process referred to as in vivo selection. We have developed a strategy for in vivo selection for liver-directed gene therapy and demonstrated that this strategy can be used in vitro to select genetically modified cells. We are now extending this in vitro work to test, in an animal model, the hypothesis that gene-modified hepatocytes with an increased capacity for glutathione production will have a growth advantage when exposed to the selection pressure of paracetamol in vivo. The secondary aim of the project is to test whether therapeutic levels of factor IX (the clotting factor deficient in Haemophilia B) can be obtained in mice using this in vivo selection strategy. Latest generation lentiviral vectors are being used for this work and the initial phase of the project involving the construction of the lentiviral vectors is underway.

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