Kupffer Cells and Not Liver Sinusoidal Endothelial Cells Prevent Lentiviral Transduction of Hepatocytes

Til, Niek P. van; Markusic, David M.; Rijt, Roos van der; Kunne, Cindy; Hiralall, Johan K.; Vreeling, Heleen; Frederiks, Wilma M.; Oude-Elferink, Ronald; Seppen, Jurgen

doi:10.1016/j.ymthe.2004.09.012

Cited by 41 publications

(37 citation statements)

References 36 publications

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“…This indicated, as noticed also by others, that lentiviral vectors may not be appropriate for liver gene transfer. 41,42,46 In summary, we showed that a single intraportal vein or tail vein administration of rAAV2-PKU-5/8 resulted in sustained therapeutic correction of the PKU mouse model, irrespective of the gender, and with no observed liver damage or toxicity associated with the rAAV transfer. The feasibility of a single i.v.…”

Section: Resultsmentioning

confidence: 62%

Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer

2005

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Phenylketonuria (PKU) is an inborn error of metabolism caused by deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) which leads to high blood phenylalanine (Phe) levels and consequent damage of the developing brain with severe mental retardation if left untreated in early infancy. The current dietary Phe restriction treatment has certain clinical limitations. To explore a long-term nondietary restriction treatment, a somatic gene transfer approach in a PKU mouse model (C57Bl/6-Pah enu2 ) was employed to examine its preclinical feasibility. A recombinant adenoassociated virus (rAAV) vector containing the murine Pah-cDNA was generated, pseudotyped with capsids from AAV serotype 8, and delivered into the liver of PKU mice via single intraportal or tail vein injections. The blood Phe concentrations decreased to normal levels (p100 mM or 1.7 mg/dl) 2 weeks after vector application, independent of the sex of the PKU animals and the route of application. In particular, the therapeutic long-term correction in females was also dramatic, which had previously been shown to be difficult to achieve. Therapeutic ranges of Phe were accompanied by the phenotypic reversion from brown to black hair. In treated mice, PAH enzyme activity in whole liver extracts reversed to normal and neither hepatic toxicity nor immunogenicity was observed. In contrast, a lentiviral vector expressing the murine Pah-cDNA, delivered via intraportal vein injection into PKU mice, did not result in therapeutic levels of blood Phe. This study demonstrates the complete correction of hyperphenylalaninemia in both males and females with a rAAV serotype 8 vector. More importantly, the feasibility of a single intravenous injection may pave the way to develop a clinical gene therapy procedure for PKU patients.

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Section: Resultsmentioning

confidence: 62%

Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer

2005

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“…GdCl 3 was injected intravenously (i.v.) at 10 mg/ kg, at 30 h and 6 h prior to plasmid injection [34]. Blood was collected by retro-orbital phlebotomy.…”

Section: Mice Injections Blood and Tissue Collectionmentioning

confidence: 99%

Prolonged expression of a lysosomal enzyme in mouse liver after Sleeping Beauty transposon‐mediated gene delivery: implications for non‐viral gene therapy of mucopolysaccharidoses

Aronovich

Bell

Belur

et al. 2007

The Journal of Gene Medicine

100

124

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“…This is in contrast to the preferential transduction of Kupffer cells by lentiviral vectors injected in the portal vein of adult mice. 20 …”

Section: Demonstration Of Gene Transfermentioning

confidence: 99%

Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats

Seppen¹,

Til²,

Rijt³

et al. 2005

Gene Ther

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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 immunogenic proteins such as UGT1A1 does not necessarily lead to tolerization.

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Kupffer Cells and Not Liver Sinusoidal Endothelial Cells Prevent Lentiviral Transduction of Hepatocytes

Cited by 41 publications

References 36 publications

Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer

Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer

Prolonged expression of a lysosomal enzyme in mouse liver after Sleeping Beauty transposon‐mediated gene delivery: implications for non‐viral gene therapy of mucopolysaccharidoses

Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats

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