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Article: Systemic production of IL-12 by naked DNA mediated gene transfer: Toxicity and attenuation of transgene expression in vivo

TitleSystemic production of IL-12 by naked DNA mediated gene transfer: Toxicity and attenuation of transgene expression in vivo
Authors
Issue Date2001
Citation
Journal of Gene Medicine, 2001, v. 3 n. 4, p. 384-393 How to Cite?
AbstractBackground: IL-12 is a potent antitumor cytokine for cancer gene therapy. Previously, we demonstrated that single systemic administration of naked DNA (encoding IL-12) could serve as a good model for in vivo evaluation of the antitumor effect of a candidate gene (unpublished data). In the present study, we propose that this gene delivery method could be a very useful model for in vivo evaluation of the toxicity of a given therapeutic gene (using IL-12 as an example). By comparing the toxicities and the effects of initial IL-12 administration on subsequent transgene expression, both IL-12 gene delivery and recombinant murine IL-12 protein (rmIL-12) administration showed similar toxicity profiles. Methods: Naked DNA encoding murine IL-12 (mIL-12) was delivered into mice by systemic administration. Toxicity profiles of mice treated with DNA or rmIL-12 were compared. Results: Systemic administration of naked DNA encoding mIL-12 resulted in very similar toxicity as rmIL-12 with respect to liver enzyme, hematological and immunological profiles. Repeated injection of mIL-12 gene did not recover a high level of mIL-12 production as the first injection. Moreover, initial mIL-12 administration resulted in inhibition of subsequent reporter gene expression with both viral and non-viral promoters (CMV, human α-antitrypsin or chicken β-actin promoter). This transgene inhibition effect was entirely mediated by IFN-γ as the transgene expression was fully recovered in IFN-y knockout mice. Conclusions: Systemic IL-12 therapy, with either a protein or gene therapy approach, resulted in comparable liver and systemic toxicities. Refractoriness of mIL-12 production by subsequent administration of mIL-12 gene was observed. The transgene attenuation effect of IL-12 pre-dosing (either by IL-12 or rmIL-12), mediated by IFN-γ, provided important insights for the design of IL-12 combination gene therapy and the improvement of gene vectors for IL-12 therapy. The present results show that simple injection of naked DNA could serve as a good model for in vivo evaluation of the toxicity of a candidate therapeutic gene. Copyright © 2001 John Wiley & Sons, Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/194122
ISSN
2015 Impact Factor: 3.246
2015 SCImago Journal Rankings: 1.025

 

DC FieldValueLanguage
dc.contributor.authorLui, VWY-
dc.contributor.authorFalo Jr, LD-
dc.contributor.authorHuang, L-
dc.date.accessioned2014-01-30T03:32:11Z-
dc.date.available2014-01-30T03:32:11Z-
dc.date.issued2001-
dc.identifier.citationJournal of Gene Medicine, 2001, v. 3 n. 4, p. 384-393-
dc.identifier.issn1099-498X-
dc.identifier.urihttp://hdl.handle.net/10722/194122-
dc.description.abstractBackground: IL-12 is a potent antitumor cytokine for cancer gene therapy. Previously, we demonstrated that single systemic administration of naked DNA (encoding IL-12) could serve as a good model for in vivo evaluation of the antitumor effect of a candidate gene (unpublished data). In the present study, we propose that this gene delivery method could be a very useful model for in vivo evaluation of the toxicity of a given therapeutic gene (using IL-12 as an example). By comparing the toxicities and the effects of initial IL-12 administration on subsequent transgene expression, both IL-12 gene delivery and recombinant murine IL-12 protein (rmIL-12) administration showed similar toxicity profiles. Methods: Naked DNA encoding murine IL-12 (mIL-12) was delivered into mice by systemic administration. Toxicity profiles of mice treated with DNA or rmIL-12 were compared. Results: Systemic administration of naked DNA encoding mIL-12 resulted in very similar toxicity as rmIL-12 with respect to liver enzyme, hematological and immunological profiles. Repeated injection of mIL-12 gene did not recover a high level of mIL-12 production as the first injection. Moreover, initial mIL-12 administration resulted in inhibition of subsequent reporter gene expression with both viral and non-viral promoters (CMV, human α-antitrypsin or chicken β-actin promoter). This transgene inhibition effect was entirely mediated by IFN-γ as the transgene expression was fully recovered in IFN-y knockout mice. Conclusions: Systemic IL-12 therapy, with either a protein or gene therapy approach, resulted in comparable liver and systemic toxicities. Refractoriness of mIL-12 production by subsequent administration of mIL-12 gene was observed. The transgene attenuation effect of IL-12 pre-dosing (either by IL-12 or rmIL-12), mediated by IFN-γ, provided important insights for the design of IL-12 combination gene therapy and the improvement of gene vectors for IL-12 therapy. The present results show that simple injection of naked DNA could serve as a good model for in vivo evaluation of the toxicity of a candidate therapeutic gene. Copyright © 2001 John Wiley & Sons, Ltd.-
dc.languageeng-
dc.relation.ispartofJournal of Gene Medicine-
dc.titleSystemic production of IL-12 by naked DNA mediated gene transfer: Toxicity and attenuation of transgene expression in vivo-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/jgm.201-
dc.identifier.pmid11529668-
dc.identifier.scopuseid_2-s2.0-0035407547-
dc.identifier.volume3-
dc.identifier.issue4-
dc.identifier.spage384-
dc.identifier.epage393-

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