Gene therapy for inherited disorders might cause an immune response to the therapeutic protein. A solution would be to introduce the gene in the fetal or neonatal period, which should lead to tolerization. Lentiviral vectors mediate long-term gene expression, and are well suited for gene therapy early in development. A model for fetal or neonatal gene therapy is the inherited disorder of bilirubin metabolism, Crigler-Najjar disease (CN). The absence of bilirubin UDP-glucoronyltransferase (UGT1A1) activity in CN patients causes high serum levels of unconjugated bilirubin and brain damage in infancy. CN is attractive for the development of gene therapy because the mutant Gunn rat closely mimics the human disease. Injection of UGT1A1 lentiviral vectors corrected the hyperbilirubinemia for more than a year in rats injected as fetuses and for up to 18 weeks in rats injected the day of birth. UGT1A1 gene transfer was confirmed by the presence of bilirubin glucuronides in bile. All animals injected with UGT1A1 lentiviral vectors developed antibodies to UGT1A1. Animals injected with green fluorescent protein (GFP) lentiviral vectors did not develop antibodies to GFP. Our results indicate that fetal and neonatal gene therapy with immuno...Continue Reading
Isolation and characterisation of a new hepatic bilirubin UDP-glucuronosyltransferase. Absence from Gunn rat liver
Characterization and tissue specificity of a monoclonal antibody against human uridine 5'-diphosphate-glucuronosyltransferase
Phenobarbital induction of cytochrome P-450 and UDP-glucuronosyltransferase in rabbit liver plasma membranes
Long term correction of bilirubin-UDP-glucuronosyltransferase deficiency in Gunn rats by administration of a recombinant adenovirus during the neonatal period.
Transplantation of Gunn rats with autologous fibroblasts expressing bilirubin UDP-glucuronosyltransferase: correction of genetic deficiency and tumor formation
Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease
Cytotoxic immune response blunts long-term transgene expression after efficient retroviral-mediated hepatic gene transfer in rat
Humoral immune response to recombinant adenovirus and adeno-associated virus after in utero administration of viral vectors in mice
Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo.
In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor.
Induction of cytotoxic T-lymphocyte responses to enhanced green and yellow fluorescent proteins after myeloablative conditioning.
Long-term correction of bilirubin UDPglucuronyltransferase deficiency in rats by in utero lentiviral gene transfer
Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic factor IX in mice.
Kupffer cells and not liver sinusoidal endothelial cells prevent lentiviral transduction of hepatocytes
X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice
In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance
Alteration of viral lipid composition by expression of the phospholipid floppase ABCB4 reduces HIV vector infectivity
Lentiviral vectors that express UGT1A1 in liver and contain miR-142 target sequences normalize hyperbilirubinemia in Gunn rats
Long-term reduction of jaundice in Gunn rats by nonviral liver-targeted delivery of Sleeping Beauty transposon
Restricted transgene persistence after lentiviral vector-mediated fetal gene transfer in the pregnant rabbit model
Adeno-associated virus vector serotypes mediate sustained correction of bilirubin UDP glucuronosyltransferase deficiency in rats
Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type I
Critical assessment of lifelong phenotype correction in hyperbilirubinemic Gunn rats after retroviral mediated gene transfer
Efficacy of AAV8-hUGT1A1 with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients.
CREs: Gene & Cell Therapy
Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.