Liver-Directed Gene Transfer in Non-Human Primates

Sullivan, Deborah E.; Dash, Srikanta; Du, Hong; Hiramatsu, Naoki; Aydin, Faruk; Kolls, Jay K.; Blanchard, James; Baskin, Gary B.; Gerber, Michael A.

doi:10.1089/hum.1997.8.10-1195

Cited by 104 publications

(62 citation statements)

References 34 publications

(26 reference statements)

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“…Besides CAR and a v integrins, a tertiary receptor-type, heparan sulfate proteoglycans (HSPG), was proposed to play a role in viral infectivity of adenovirus types 2 and 5. 4 In vivo, systemic administration of Ad5-derived replication-deficient vectors in rodents and non-human primates results in sequestration of the virus in the liver with 95% of measurable transduction in liver hepatocytes 5,6 and uptake by Kupffer cells. 7 Whereas the exact mechanism still needs to be elucidated, liver tropism represents a barrier for selective infection of non-liver target tissue, for example in the context of gene-based cancer therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies

et al. 2007

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Previously, we have identified a tumor cell-specific peptide, HEW, by panning of phage display libraries on the human colorectal cancer cell line WiDr. In this report we demonstrate that this peptide can modify the infection properties of adenovirus vectors. Increased infectivity of replication-deficient adenovirus 5 vectors in WiDr cells was observed upon genetic insertion of the HEW peptide in the HI loop of the fiber knob. Moreover, whereas the coxsackie and adenovirus receptor (CAR)-ablating fiber mutation S408E abolished apparent infection in CAR-positive WiDr cells, the insertion of HEW completely restored infectivity toward these cells in vitro. To assess whether the de-and re-targeted infection profile was maintained in vivo, the fiber-modified adenovirus vectors were injected intratumorally or intravenously in WiDr tumor-bearing Swiss nu/nu mice. No significant differences in efficiency of infection could be observed suggesting alternative viral uptake mechanisms in vivo. Next, we have included the fiber shaft mutation S* in our studies, which was described to confer a de-targeted phenotype in vivo. Reduced gene transfer due to the S* mutation both in vitro and in vivo could be confirmed. Insertion of HEW in the HI knob loop of shaft-mutated fiber, however, did not rescue infectivity in target cells neither in vitro nor in vivo. We demonstrate the efficient ligand-mediated re-targeting of adenoviral vector infection to the human cancer cell line WiDr. The lack of apparent re-targeting in the in vivo situation is described.

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Section: Introductionmentioning

confidence: 99%

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies

et al. 2007

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“…They integrate stably into the genome of the host cell and are therefore potential vectors for long-term expression of therapeutic genes. Moreover, they overcome most of the drawbacks of adenoviral vectors, such as toxicity and immunogenicity [29]. Another limitation of adenoviral delivery of PDX1 is that it results in only about one copy per liver cell.…”

Section: Introductionmentioning

confidence: 99%

Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach

et al. 2006

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Aims/hypothesis We examined a clinical model of ex vivo transdifferentiation of primary adult hepatocytes to insulinsecreting cells for the treatment of type 1 diabetes. Materials and methods Isolated rat hepatocytes were transduced in primary culture with a human lentivirus containing pancreatic duodenal homeobox 1 (PDX1, now known as insulin promoter factor 1, homeodomain transcription factor [IPF1]). Insulin expression and secretion of the newly engineered cells were assessed in vitro by RT-PCR, in situ hybridisation, immunostaining and radioimmunoassay. PDX1-transduced hepatocytes were further studied in vivo by injecting them under the renal capsule of diabetic SCID mice. Results Isolated rat hepatocytes were efficiently transduced with the lentiviral vector, as assessed by green fluorescent reporter gene expression. The transduced cells exhibited insulin at both mRNA (RT-PCR, in situ hybridisation) and protein levels (immunostaining and radioimmunoassay). Moreover, insulin secretion by the engineered cells was dependent on glucose and sulfonylurea. Other beta cell genes, including those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (Slc2a2), glucokinase (Gck), ATP-binding cassette, sub-family C (CFTR/ MRP), member 8 (Abcc8), the potassium inwardly-rectifying channel, subfamily J, member 11 (Kcnj11) and proprotein convertase subtilisin/kexin type 1 (Pcsk1) were also expressed. The PDX1-transduced hepatocytes expressed several pancreatic transcription factors related to early pancreatic endocrine development (endogenous Pdx1, 6 transdifferentiated liver cells under the renal capsule of seven streptozotocin-induced diabetic SCID mice resulted in significant reduction of nonfasting blood glucose levels from 30.7 ± 1.3 to 8.7 ± 3.7 mmol/l (mean ± SEM, p=0.01), in 6 to 8 weeks. Removal of the graft resulted in severe hyperglycaemia. Conclusions/interpretation Ex vivo lentiviral-mediated PDX1 expression in isolated adult liver cells represents a potential model for type 1 diabetes mellitus therapy.

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“…4,5 Although, the inhibition of T cell function in the liver is partially effective in limiting the hepatotoxic effects of viral vectors, the prolonged use of immune suppressants during hepatic gene therapy protocols may predispose patients to opportunistic infections. [6][7][8] In addition, the potential for greatly enhanced liver injury exists when analgesics are concurrently administered during hepatic gene therapy. Acetaminophen is a widely used nonprescription analgesic and antipyretic that causes severe cetrilobular hepatic necrosis and eventual liver failure, even in the absence of known risk factors such as pre-existing liver disease, overdose, malnourishment, or excess alcohol consumption.…”

Section: Introductionmentioning

confidence: 99%

Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury

et al. 1999

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Liver-Directed Gene Transfer in Non-Human Primates

Cited by 104 publications

References 34 publications

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies

Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach

Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury

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