RGD Reference Report - Successful treatment of UGT1A1 deficiency in a rat model of Crigler-Najjar disease by intravenous administration of a liver-specific lentiviral vector. - Rat Genome Database

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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.
RGD ID: 13432067
Pubmed: PMID:16337205   (View Abstract at PubMed)
DOI: DOI:10.1016/j.ymthe.2005.09.022   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Crigler-Najjar syndrome  IMP 13432067 RGD 
Crigler-Najjar syndrome  ISOUGT1A1 (Homo sapiens)13432067; 13432067 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
increased circulating bilirubin level  IAGP 13432067; 13432067; 13432067 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Ugt1a1  (UDP glucuronosyltransferase family 1 member A1)
Ugt1a1j  (UDP glucuronosyltransferase family 1 member A1, jaundice mutant)

Genes (Mus musculus)
Ugt1a1  (UDP glucuronosyltransferase 1 family, polypeptide A1)

Genes (Homo sapiens)
UGT1A1  (UDP glucuronosyltransferase family 1 member A1)

Strains
Gunn-Ugt1a1j/BluHsd  (Gunn rat)


Additional Information