Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model

Suzuki, Koichi; Aoki, Kazunori; Ohnami, Shumpei; Yoshida, Kimiko; Kazui, Teruhisa; Kato, Naoya; Inoue, Kazuaki; Kohara, Michinori; Yoshida, Teruhiko

doi:10.1038/sj.gt.3301949

Cited by 39 publications

(37 citation statements)

References 49 publications

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“…11,12 Instead, adenovirus transduce sinusoidal cells such as Kupffer cells, HSCs or endothelial cells. 30,31 It has been suggested that transduction of hepatocytes is affected in cirrhotic livers at the access from the blood to the space of Disse and at the interaction of the vector with the hepatocyte. The passage from the blood into the space of Disse is through the fenestrae of sinusoidal cells.…”

Section: Discussionmentioning

confidence: 99%

“…This could be achieved with adenoviral vectors. 30,31 Alternatively, hepatocytes could be transduced by AAV vectors to secrete therapeutic proteins that target HSCs. Altogether, our data show that AAV1 with a liver-specific promoter injected intra-arterially should be an ideal vector for long-term expression of therapeutic proteins in fibrotic livers.…”

Section: Discussionmentioning

confidence: 99%

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AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers

et al. 2011

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In liver cirrhosis, abnormal liver architecture impairs efficient transduction of hepatocytes with large viral vectors such as adenoviruses. Here we evaluated the ability of adeno-associated virus (AAV) vectors, small viral vectors, to transduce normal and cirrhotic rat livers. Using AAV serotype-1 (AAV1) encoding luciferase (AAV1Luc) we analyzed luciferase expression with a CCD camera. AAV1Luc was injected through the hepatic artery (intra-arterial (IA)), the portal vein (intra-portal (IP)), directly into the liver (intra-hepatic (IH)) or infused into the biliary tree (intra-biliar). We found that AAV1Luc allows long-term and constant luciferase expression in rat livers. Interestingly, IP administration leads to higher expression levels in healthy than in cirrhotic livers, whereas the opposite occurs when using IA injection. IH administration leads to similar transgene expression in cirrhotic and healthy rats, whereas intra-biliar infusion is the least effective route. After 70% partial hepatectomy, luciferase expression decreased in the regenerating liver, suggesting lack of efficient integration of AAV1 DNA into the host genome. AAV1Luc transduced mainly the liver but also the testes and spleen. Within the liver, transgene expression was found mainly in hepatocytes. Using a liver-specific promoter, transgene expression was detected in hepatocytes but not in other organs. Our results indicate that AAVs are convenient vectors for the treatment of liver cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers

et al. 2011

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“…7 Baculovirus infection activates tumor necrosis factor-a, interleukin (IL)-1a and IL-1b expression in primary hepatocyte cultures, 8 probably due to the presence of small numbers of Kupffer cells in the culture population, 9 while adenoviral vector expression of interferon (IFN)-a and IFN-g in the liver of rats with hepatic fibrosis improves the symptoms of hepatic fibrosis. 10,11 In the present study, we used a mouse model of hepatic fibrosis to investigate the therapeutic efficacy of the baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) on immune response induction, and the suppression of liver injury and fibrosis in vivo. The results of the present study provide the first evidence of the feasibility of using baculovirus to treat LC.…”

Section: Introductionmentioning

confidence: 99%

Baculovirus-mediated interferon alleviates dimethylnitrosamine-induced liver cirrhosis symptoms in a murine model

et al. 2008

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The wild-type baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) infects a range of mammalian cell types in vitro but does not replicate in these cells. The current study investigated the in vivo effect of AcMNPV in the mouse model of liver cirrhosis induced by the mutagen dimethylnitrosamine. Intraperitoneal injection of AcMNPV induced an immune response. The baculovirus was taken up by the liver and spleen where it suppressed liver injury and fibrosis through the induction of interferons. This study presents the first evidence of the feasibility of using baculovirus to treat liver cirrhosis. Gene Therapy (2008) 15, 990-997;

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“…In the conventional regimen of IFN clinical trials, the recombinant IFN-a protein is systemically administrated through subcutaneous, intravenous or intramuscular routes. However, pharmacokinetic studies have indicated that the half-life of the IFN-a protein is 3 h in the blood circulation and only 0.01% of subcutaneously injected IFN-a can reach the target sites (Salmon et al, 1996;Suzuki et al, 2003), indicating that IFN-a protein delivery might be insufficient and/or at an unsustainable level in the tumour site. This may be the major reason why the previous trials based on the conventional IFN-a therapy failed to show an adequate antitumour effect.…”

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confidence: 99%

“…This may be the major reason why the previous trials based on the conventional IFN-a therapy failed to show an adequate antitumour effect. By contrast, improved therapeutic effect and safety are expected for IFN-a gene transfer, because it allows an increased and sustained local concentration of this cytokine in the target sites while minimising unnecessary systemic distribution (Suzuki et al, 2003;Hatanaka et al, 2004). In fact, it has been reported that direct IFN-a gene transfer into tumours suppressed growth of various cancers such as breast cancer, prostate cancer, renal cancer, hepatocellular carcinoma, basal cell carcinoma and leukaemia (Zhang et al, 1996;Coleman et al, 1998;Hottiger et al, 1999;Iqbal Ahmed et al, 2001).…”

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confidence: 99%

Adenovirus-mediated interferon α gene transfer induces regional direct cytotoxicity and possible systemic immunity against pancreatic cancer

Ohashi¹,

Yoshida²,

Kushida³

et al. 2005

Br J Cancer

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We previously demonstrated a characteristically high sensitivity of pancreatic cancer cells to interferon alpha (IFN-a) gene transfer, which induced a more prominent growth suppression and cell death in pancreatic cancer cells than in other types of cancers and normal cells. The IFN-a protein can exhibit both direct cytotoxicity and indirect immunological antitumour activity. Here, we dissected and examined the two mechanisms, taking advantage of the fact that IFN-a did not show any cross-species activity in its in vivo effect. When a human IFN-a adenovirus was injected into subcutaneous xenografts of human pancreatic cancer cells in nude mice, tumour growth was significantly suppressed due to cell death in an adenoviral dose-dependent manner. The IFN-a protein concentration was markedly increased in the injected subcutaneous tumour, but leakage of the potent cytokine into the systemic blood circulation was minimal. When a mouse IFN-a adenovirus was injected into the same subcutaneous tumour system, all mice showed significant tumour inhibition, an effect that was dependent on the indirect antitumour activities of IFN-a, notably a stimulation of natural killer cells. Moreover, in this case, tumour regression was observed not only for the injected subcutaneous tumours but also for the untreated tumours at distant sites. This study suggested that a local IFN-a gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its dual mechanisms of antitumour activities and lack of significant toxicity.

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Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model

Cited by 39 publications

References 49 publications

AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers

AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers

Baculovirus-mediated interferon alleviates dimethylnitrosamine-induced liver cirrhosis symptoms in a murine model

Adenovirus-mediated interferon α gene transfer induces regional direct cytotoxicity and possible systemic immunity against pancreatic cancer

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