Adenovirus–mediated in vivo gene transfer and expression in normal rat liver

Jaffe, Howard; Danel, Claire; Longenecker, Glenn; Metzger, Meredith B.; Setoguchi, Yasuhiro; Rosenfeld, Melissa A.; Gant, Timothy W.; Thorgeirsson, Snorri S.; Stratford-Perricaudet, Leslie D.; Perricaudet, Michel; Pavirani, Andréa; Lecocq, Jean‐Pierre; Crystal, Ronald G.

doi:10.1038/ng0892-372

Cited by 437 publications

(232 citation statements)

References 49 publications

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“…For example, we are aware of no studies that have investigated this in hepatocytes, a cell that is readily infected by adenovirus in vitro [6][7][8] and in vivo. [1][2][3][4][5] Our data suggest that the interaction between adenovirus fiber and a fiber receptor are important for infection. This conclusion is consistent with studies carried out in a number of easily infected cell lines.…”

Section: Discussionmentioning

confidence: 99%

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An interaction between penton base and αv integrins plays a minimal role in adenovirus-mediated gene transfer to hepatocytes in vitro and in vivo

et al. 1998

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Studies in cultured cell lines have shown that adenovirus tion of hepatocytes, even though the mutation impaired infection involves binding of adenovirus fiber to its cell surinfection of HeLa cells. Hepatocytes had undetectable face receptor and binding of penton base to ␣v integrins.amounts of ␣v integrins on their cell surface and showed However, much less is known about the role of these interno specific adherence to vitronectin, the natural substrate actions in cells that are targets for adenovirus-mediated of ␣v integrins. Adenovirus with an intact penton base gene transfer. Earlier work showed that hepatocytes are enhanced infection of liver following intravenous injection, readily infected by adenovirus, making them an attractive but only by three-fold as compared with virus in which the target for gene therapy in several diseases. We found that integrin-binding motif was disrupted. These studies sugaddition of fiber protein blocked adenovirus infection of prigest that interactions between cell surface integrins and mary cultures of hepatocytes. This suggests an important penton base are not required for adenovirus infection of role for fiber and its receptor. However, mutation of the hepatocytes in vitro, but the interaction enhances infection integrin-binding motif in penton base did not inhibit infecto a small degree in vivo.

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Section: Discussionmentioning

confidence: 99%

“…For example, after intravenous injection of recombinant adenovirus, gene transfer to the liver is most efficient. [1][2][3][4][5] Gene transfer to hepatocytes is also efficient in vitro. [6][7][8] However, the mechanisms by which adenoviruses infect hepatocytes has received little attention.…”

Section: Introductionmentioning

confidence: 99%

An interaction between penton base and αv integrins plays a minimal role in adenovirus-mediated gene transfer to hepatocytes in vitro and in vivo

et al. 1998

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“…Experimentally, regional delivery to the hepatic parenchyma of small animals using Ad vectors can be accomplished by intravenous, intraportal, or intrahepatic arterial injection of vector. [42][43][44]55 Importantly, there is minimal risk from the Ad vector per se, with systemic (i.v.) administration of Յ10 9 PFU Ad vectors to mice inducing only mild, self-limited inflammation within the hepatic parenchyma.…”

Section: Discussionmentioning

confidence: 99%

Regional treatment of hepatic micrometastasis by adenovirus vector-mediated delivery of interleukin-2 and interleukin-12 cDNAs to the hepatic parenchyma

et al. 1999

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We hypothesize that adenovirus (Ad) vector-mediated delivery of the human interleukin-2 (IL-2) cDNA (AdIL2) or the murine IL-12 cDNA heterodimer (AdIL12) would produce high concentrations of cytokines in the local hepatic milieu to induce host responses sufficient to inhibit the growth of experimental colon carcinoma-derived hepatic metastases. Ad vectors administered intravenously, which is a route known to deliver Ͼ90% of the vector to the hepatic parenchyma, achieved significant levels of each cytokine locally, with minimal levels in the sera. To examine the therapeutic effect, the AdIL2 and AdIL12 vectors were evaluated in a hepatic metastasis model that was established by injecting 3 ϫ 10 4 cells from the poorly immunogenic syngeneic C26 colon carcinoma cell line into the right lobe of the livers of BALB/c mice. Animals received AdIL2, AdIL12, or control virus (10 8 plaque-forming units each) intravenously for 2 days after tumor implantation, and tumor growth was compared with naive controls. The AdNull control tumors measured 116 Ϯ 25 mm 2 at 2 weeks. The control virus showed no significant antitumor effect. In marked contrast, both AdIL2 and AdIL12 vectors that were delivered regionally had significant antitumor effects, with AdIL2-treated animals having an average tumor size of 16 Ϯ 8 mm 2 ; AdIL12-treated tumors measured 6 Ϯ 6 mm 2 (P Ͻ .01, both compared with control). Both the AdIL2 and AdIL12 vectors provided a significant survival advantage by log-rank analysis (P Ͻ .01), but only AdIL12 translated into an increase in mean survival from 27 (naive control) to 37 days. To evaluate whether these antitumor effects were T-cell-mediated, splenocytes from AdIL2-treated, AdIL12-treated, and naive control groups were stimulated in vitro with ␥-irradiated C26 tumor cells for 5 days and tested for C26 tumor cell cytolysis by an in vitro cytotoxicity assay. Splenocytes from both AdIL2-and AdIL12-treated animals showed a dose-dependent, T-cell-mediated, specific cytolysis of CT26 cells. AdIL12 and to a lesser extent AdIL2 induced natural killer cell activity, as determined by a dose-dependent increase in lysis of the natural killer-specific target cell YAC-1. Overall, these data suggest that regional Ad-mediated delivery of IL-2 and IL-12 cDNAs may be useful for local tumor control and may warrant further investigation as a potentially useful adjuvant for the treatment of hepatic micrometastasis.

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“…21,22 However, it turned out rapidly that transgene expression was transient due to cytotoxic immune elimination of transduced hepatocytes. The immune response was mainly directed against adenoviral proteins although a response against the transgene product was present as well, depending on the mouse strain.…”

Section: Adenoviral Vectorsmentioning

confidence: 99%