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

Vivian Wai Yan Lui, Louis Domenic Falo, Leaf Huang

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Background: 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DNA (encoding IL-12) could serve as a good model for in vivo evaluation of the antitumor effect of a candidate gene (unpublished data).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.

Original languageEnglish (US)
Pages (from-to)384-393
Number of pages10
JournalJournal of Gene Medicine
Volume3
Issue number4
DOIs
StatePublished - Jul 2001
Externally publishedYes

Keywords

  • Gene therapy
  • IFN-γ
  • IL-12 toxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Systemic production of IL-12 by naked DNA mediated gene transfer: Toxicity and attenuation of transgene expression in vivo'. Together they form a unique fingerprint.

Cite this