Toxicity of a First-Generation Adenoviral Vector in Rhesus Macaques

Lozier, Jay N.; Csákó, György; Mondoro, Traci Heath; Krizek, Dennis M.; Metzger, Mark E.; Costello, Rene; Vostal, Jaroslav G.; Rick, Margaret E.; Donahue, Robert E.; Morgan, Richard A.

doi:10.1089/10430340152712665

Cited by 112 publications

(102 citation statements)

References 35 publications

(21 reference statements)

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“…30 Finally, intravenous injection of lethal doses of FGAd in nonhuman primates causes diffuse endothelial damage that may lead to platelet activation, aggregation and depletion. 19,31 There is a nonlinear dose-response to Ad vector transgene expression. [32][33][34][35] Sequestration of an Ad vector by Kupffer cells may underlie this threshold effect.…”

Section: Long-term Phenotypic Correction By a Helper-dependent Adenovmentioning

confidence: 99%

Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

et al. 2006

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We examined the efficacy and host response to the adenovirus (Ad)-mediated delivery of human apolipoprotein A-I (APOA1) gene to the liver of APOA1 À/À mice. Administration of a first-generation vector (FGAd-AI) resulted in a transient appearance of APOA1 in plasma and induced an anti-APOA1 antibody titer, whereas treatment with a helperdependent vector (HDAd-AI) resulted in sustained APOA1 expression without inducing an antibody titer. With these results, we studied the effects of FGAd vectors on APOAI expression by HDAd-AI vector. Co-treatment with an FGAd vector inhibited HDAd-AI-mediated APOA1 expression independent of transgene cassettes, but only FGAd-AI induced a humoral response. Furthermore, APOA1 mRNA levels in mice co-treated with FGAd vectors were much lower than those expected from the vector copy number, suggesting that DNA of FGAd vectors interferes with the HDAd-AI vector's APOA1 promoter. A single treatment with an HDAd-AI vector produced a supraphysiological plasma APOA1 level that gradually declined to about half the normal human level over the course of 2 years, associated with a plasma cholesterol level that is persistently higher than that in controls. This investigation provides the proof of principle that liver-directed HDAd gene delivery is effective for the long-term phenotypic correction of monogenic hypoalphalipoproteinemia.

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Section: Long-term Phenotypic Correction By a Helper-dependent Adenovmentioning

confidence: 99%

Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

et al. 2006

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“…19 NK4 is a secretory protein, so it is not necessary for the vector to limit transduction to cancer cells. The adenovirus vector can show toxicity in the liver, muscle and lung when it is injected at high concentrations, 26 and it can also cause host immune responses when administered intravenously. 27 Use of minimal vector concentration to express maximum transfected gene product is necessary.…”

Section: Discussionmentioning

confidence: 99%

Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice

et al. 2005

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NK4, a 4-kringle fragment of hepatocyte growth factor (HGF), is an HGF antagonist that also acts as an angiogenesis inhibitor. NK4 strongly inhibits the infiltration, metastasis, and tumor growth of pancreatic cancer. The aim of our study was to evaluate the antitumor effect of adenovirus-mediated NK4 gene transfer to the liver on hepatic metastasis of pancreatic cancer in vivo. We constructed recombinant adenoviral NK4 (Ad-NK4), which encodes a secreted form of human NK4. Intrasplenic injection of Ad-NK4 induced high and relatively maintained expression of NK4 protein in the liver and suppressed the number and growth of metastatic foci in the liver in a nude mouse model. Microscopically, central necrosis was found even in small metastatic foci in Ad-NK4 treated mice. Immunohistochemical analysis of metastatic tumors showed a remarkable decrease in microvessel density and an increase in the number of apoptotic tumor cells after treatment with Ad-NK4. These results indicate that intraportal injection of Ad-NK4 may be a useful therapeutic modality for the clinical control of hepatic metastasis in pancreatic cancer. ' 2005 Wiley-Liss, Inc.Key words: gene therapy; NK4; HGF antagonist; angiogenesis inhibitor; pancreatic cancer; hepatic metastasis; recombinant adenovirus Pancreatic cancer remains one of the most malignant neoplasms. The disease is diagnosed frequently at an advanced stage, and only 3% of patients survive 5 years. 1 Pancreatic cancer has a high rate of local and systemic recurrence, including liver metastasis, peritoneal dissemination and retroperitoneal recurrence. 2 There is no effective treatment for this disease. Radical resection has only a limited effect for the disease, 3 but even after curative resection of the primary tumor, liver metastasis occurs frequently and constitutes a major course of this disease. 2,4 Generally, micrometastasis to the liver seems to have already occurred in most patients when pancreatic cancer is diagnosed. 5 Pancreatic cancer is highly resistant to the chemotherapy and radiation protocols available currently. Even gemcitabine, which has become the standard drug used for metastatic disease, does not improve median survival. One factor underlying the aggressive local and early systemic tumor growth may be rapid tumor neoangiogenesis, which results in an abundant blood supply. Tumor-induced neoangiogenesis is a common phenomenon during growth, particularly in tumors larger than 1-2 mm in diameter. 6,7 We showed previously that pancreatic cancer cells frequently overexpress c-Met/hepatocyte growth factor (HGF) receptor and that HGF plays important roles in the mitogenic, motogenic and morphogenic activities of these cells. We also identified and prepared NK4 as an antagonist of HGF. 8,9 NK4 is composed of the N-terminal hairpin and 4 kringle domains of HGF. NK4 binds c-Met/HGF receptor but does not induce tyrosine phosphorylation of c-Met. NK4 is a potent antiangiogenic agent and antagonizes not only HGF-induced angiogenesis but also that of other angiogenic factors suc...

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“…[48][49][50] Macrophages and DCs have been implicated as the source of these cytokines. Within 2 h of intravenous administration of the vector, adenovirus particles are observed in the spleen in the macrophage/DC-rich marginal zone region, suggesting that these cells are the primary source of the acute inflammatory response.…”

Section: Immunity To Viral Vectors K Jooss and N Chirmulementioning

confidence: 99%

Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy

2003

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Toxicity of a First-Generation Adenoviral Vector in Rhesus Macaques

Cited by 112 publications

References 35 publications

Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice

Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy

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