A hypoxia-inducible vigilant vector system for activating therapeutic genes in ischemia

Yao Liang Tang, Y. Tang, Y. C. Zhang, A. Agarwal, H. Kasahara, K. Qian, L. Shen, M. I. Phillips

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Hypoxia represents an endogenous pathophysiological signal underlying cell growth, adaptation and death in a variety of diseases, including ischemic heart diseases, stroke and solid tumors. A vigilant vector system depends on a gene switch which can sense the hypoxia signal occurring in ischemic events and turn on/off protective gene expressions when necessary. This system uses the oxygen-dependent degradation domain derived from hypoxia-inducible factor 1α as the hypoxia sensor and a double-vector system as signal amplifier. For treating ischemic heart diseases, a cardiac-specific MLC-2v promoter is used to deliver transgenes specifically to the heart. When tested in cardiomyocyte cultures, it produced a rapid and robust gene induction upon exposure to low oxygen. In a mouse model for myocardial infarction, the vigilant vectors turned on therapeutic genes such as heme oxygenase-1 in response to ischemia, significantly reduced apoptosis in the infarct area and improved cardiac functions. The hypoxia-regulated gene transfer afforded by the vigilant vectors may provide a powerful tool for delivering therapeutic proteins specifically to ischemic tissues with optimal physiological control.

Original languageEnglish (US)
Pages (from-to)1163-1170
Number of pages8
JournalGene Therapy
Volume12
Issue number15
DOIs
StatePublished - Aug 1 2005

Keywords

  • Heart myocardial ischemia
  • Hypoxia
  • Ischemic diseases
  • Regulatable gene delivery

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Tang, Y. L., Tang, Y., Zhang, Y. C., Agarwal, A., Kasahara, H., Qian, K., Shen, L., & Phillips, M. I. (2005). A hypoxia-inducible vigilant vector system for activating therapeutic genes in ischemia. Gene Therapy, 12(15), 1163-1170. https://doi.org/10.1038/sj.gt.3302513