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 language | English (US) |
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Pages (from-to) | 1163-1170 |
Number of pages | 8 |
Journal | Gene Therapy |
Volume | 12 |
Issue number | 15 |
DOIs | |
State | Published - Aug 2005 |
Keywords
- Heart myocardial ischemia
- Hypoxia
- Ischemic diseases
- Regulatable gene delivery
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics