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Successful treatment of UGT1A1 deficiency in a rat model of Crigler-Najjar disease by intravenous administration of a liver-specific lentiviral vector.

Authors: van der Wegen, Pascal  Louwen, Rogier  Imam, Ali M  Buijs-Offerman, Ruvalic M  Sinaasappel, Maarten  Grosveld, Frank  Scholte, Bob J 
Citation: van der Wegen P, etal., Mol Ther. 2006 Feb;13(2):374-81. Epub 2005 Dec 5.
Pubmed: (View Article at PubMed) PMID:16337205
DOI: Full-text: DOI:10.1016/j.ymthe.2005.09.022

Treatment of congenital and acquired liver disease is one of the main issues in the field of gene therapy. Self-inactivating lentiviral vectors have several potential advantages over alternative systems. We have constructed a self-inactivating lentiviral vector (LV-ALBUGT) that expresses the human bilirubin UDP-glucuronosyltransferase (UGT1A1) from a liver-specific promoter. UGT1A1 is involved in the clearance of heme metabolites in the liver. This enzyme is deficient in Crigler-Najjar disease, a recessive inherited disorder in humans characterized by chronic severe jaundice, i.e., high plasma bilirubin levels. Gunn rats suffer from the same defect and are used as an animal model of this disease. We have treated juvenile Gunn rats by single intravenous injection with the LV-ALBUGT vector. Over 1 year after treatment with the highest dose (5 x 10(8) transducing units), we observed a stable reduction of bilirubin levels to near normal levels and normal secretion of bilirubin conjugates in the bile, in contrast to untreated animals. In situ hybridization showed expression of the therapeutic gene in more than 30% of liver parenchymal cells. Thus, we demonstrate stable and complete clinical remission of a congenital metabolic liver disease in an animal model, after systemic administration of a therapeutic lentiviral vector.


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CRRD Object Information
CRRD ID: 13432067
Created: 2017-09-18
Species: All species
Last Modified: 2017-09-18
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.