O0008 SUCCESSFUL TREATMENT OF CRIGLER-NAJJAR DISEASE BY INTRAVENOUS APPLICATION OF A LIVER-SPECIFIC LENTIVIRAL VECTOR IN A RAT MODEL.

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Introduction: Treatment of congenital and acquired liver disease is one of the main issues in the field of gene therapy. HIV-1 derived lentiviral vectors of the latest generation have several potential advantages over alternative systems. We have tested such a vector in a rat model (Gunn rat) of Crigler-Najjar disease (CN). CN is a recessive inherited disorder in humans characterized by chronic severe jaundice. CN is caused by mutations in the bilirubin UDP glycosyltransferase gene (hUGT1A1) that is involved in the clearance of heme metabolites in the liver. Present treatment by light therapy is cumbersome and insufficient. The only known effective remedy is liver transplantation, which requires high-risk surgery and cyclosporin treatment. Therefore, gene therapy is considered as an alternative. Methods: We have constructed and produced a self-inactivating VSV-G pseudotyped lentiviral vector LV ALBUGT, which is designed to express the human UGT1A1 gene specifically in liver parenchymal cells. Juvenile Gunn rats were treated with this preparation by intravenous injection (108–109 transforming units). Results: Eight weeks after treatment with the highest vector dose we observed a complete normalisation of bilirubin levels, and normal secretion of bilirubin conjugates in the bile, in contrast to untreated animals. In situ hybridisation showed expression of the therapeutic gene in up to thirty percent of liver parenchymal cells. No adverse effects, such as transient inflammation morbidity or mortality, were observed. Conclusion: To our knowledge this is the first demonstration in an animal model of complete remission of a congenital liver disease, after systemic application of a lentiviral vector. These encouraging results suggest that clinical application of this vector would be feasible