Recombinant adeno-associated virus vector: Is it ideal for gene delivery in liver transplantation?

Yang, Zhenfan; Wu, Xiaobing; Tsui, Ting Y.; Hou, Yong; Luk, John M.; Fan, Sheung‐Tat

doi:10.1053/jlts.2003.50058

Cited by 4 publications

(4 citation statements)

References 20 publications

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“…We further elucidated the molecular mechanisms of rAAV-HGFK1 in vitro in both MECs and tumor cells. Our data showed that rAAV-HGFK1 produced sustained HGFK1 expression in vivo, inhibited tumor growth and metastasis, and significantly prolonged the survival time of HCC-bearing rats.The AAV vector system has several advantages as a gene delivery scheme, including long-term transgene expression (22,29), and low pathogenicity and immunogenicity (30,31). The present study showed that expression of HGFK1 remained detectable at 120 days after administration of rAAV-HGFK1.…”

Section: Discussionsupporting

confidence: 50%

The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

Shen¹,

Yang

Gao³

et al. 2008

Cancer Research

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The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAV-HGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G 0 -G 1 phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and B fibroblast growth factor (bFGF)/B fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH 2 -kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC. [Cancer Res 2008;68(2):404-14]

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Section: Discussionsupporting

confidence: 50%

The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

Shen¹,

Yang

Gao³

et al. 2008

Cancer Research

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“…This approach has also been demonstrated using AAV vectors. Yang et al first described the use of AAV-mediated gene delivery during SCS in a rat liver transplant model in 2003 ( 11 ). In that study, the authors demonstrated successful expression of transgene CTLA4-Ig in the transplanted liver for up to 180 days.…”

Section: Discussionmentioning

confidence: 99%

AAV9-mediated gene delivery to liver grafts during static cold storage in a rat liver transplant model

et al. 2023

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IntroductionRecombinant adeno-associated virus (rAAV) is a novel strategy used clinically for gene delivery, but has not been characterized in the context of organ transplantation. We sought to determine the efficacy of rAAV-mediated gene delivery during static cold storage (SCS) prior to liver transplantation.MethodsA triple-plasmid transfection protocol was used to produce rAAV subtype-9 vectors containing firefly luciferase genomes in HEK293 cells. Lewis rat liver grafts were flushed and stored in cold HTK solution. Three experimental groups received rAAV at different doses, administered via the portal vein as a bolus during SCS. A control group did not receive rAAV (N = 2). Recipients then underwent syngeneic liver transplantation. Bioluminescence imaging to quantify in vivo luciferase expression was performed on post-operative days 7, 14, 28, and 56.ResultsControl animals demonstrated no bioluminescent activity, while animals receiving rAAV-treated livers had increasing bioluminescence, peaking at four weeks but sustained to the eight-week endpoint. This result was confirmed by experimental endpoint tissue luciferase activity assay.DiscussionrAAV mediates gene transduction in liver grafts when administered during SCS and has potential for gene therapy applications in solid organ transplantation.

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“…Besides muscle tissue, the high‐protein producing liver is an important target for systemic in vivo gene therapy. After transfection with viral vectors, high and long‐lasting expression has been demonstrated in several studies 1–4. On the way to clinical use, however, viral vectors have been associated with several problems, which are still unsolved 5–8.…”

Section: Introductionmentioning

confidence: 99%

AAV plasmid DNA simplifies liver‐directed in vivo gene therapy: comparison of expression levels after plasmid DNA‐, adeno‐associated virus‐ and adenovirus‐mediated liver transfection

Doenecke¹,

Krömer²,

Scherer³

et al. 2010

The Journal of Gene Medicine

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BackgroundSuccessful liver gene therapy depends on efficient gene transfer techniques and long‐lasting gene expression after successful transfer. Over the last decades, important progress has been made with the introduction of viral vectors using animal models, although their use is hampered by a complex and costly preparation compared to the simple and cost‐effective preparation of plasmid DNA. These problems become even more critical when considering the application of viral vectors in human gene therapy and gene therapy trials. In a previous study, we were able to show that the hydrodynamics‐based gene transfer of plasmid‐DNA, containing the adeno‐associated‐virus specific inverted terminal repeats (AAV‐ITR), prolongs gene expression in the liver, although it remained unclear whether plasmid gene transfer could achieve similar expression levels compared to viral‐vector gene transfer.MethodsRat livers were transfected in‐vivo with AAV‐ITR‐containing plasmid‐DNA using a modified hydrodynamics‐based procedure. Expression levels were monitored thereafter and compared with expression levels after viral‐vector gene transfer.ResultsA high and stable long‐term expression was achieved after in vivo transfection of rat livers with AAV‐ITR‐containing plasmids. The expression course resembled that after AAV‐mediated gene transfer, and the expression was at least as high, and lasted as long, compared to recombinant AAV‐mediated gene transfer.ConclusionsWe consider AAV‐ITR‐containing plasmids as a simple and cost‐effective alternative to recombinant viral vectors, especially for liver‐directed gene therapy in rodents. With ongoing progress in gene transfer methods for naked DNA, these plasmids may also become a successful alternative to recombinant viral vectors in human gene therapy. Copyright © 2010 John Wiley & Sons, Ltd.

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Recombinant adeno-associated virus vector: Is it ideal for gene delivery in liver transplantation?

Cited by 4 publications

References 20 publications

The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

AAV9-mediated gene delivery to liver grafts during static cold storage in a rat liver transplant model

AAV plasmid DNA simplifies liver‐directed in vivo gene therapy: comparison of expression levels after plasmid DNA‐, adeno‐associated virus‐ and adenovirus‐mediated liver transfection

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