Journal
GENE THERAPY
Volume 16, Issue 1, Pages 127-135Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2008.146
Keywords
ischemia-inducible; polymer carrier; myocardial infarction; apoptosis; angiogenesis
Categories
Funding
- NIH [HL071541, HL65477]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL065477, R01HL071541] Funding Source: NIH RePORTER
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The development of clinically beneficial myocardial gene therapy has been slowed by reliance on the use of viral carriers and non-physiologic, constitutive gene expression. To specifically address these issues, we have developed a non-viral gene carrier, water-soluble lipopolymer (WSLP), and an ischemia-inducible plasmid construct expressing vascular endothelial growth factor (VEGF), pRTP801-VEGF, to treat myocardial ischemia and infarction. Rabbits underwent ligation of the circumflex artery followed by injection of (a) an ischemia-inducible VEGF gene construct in a WSLP carrier; (b) a constitutively expressed, or unregulated, SV-VEGF gene construct in a WSLP carrier; (c) WSLP carrier alone; or (d) no injection therapy. Following 4 weeks treatment, ligation alone resulted in infarction of 48 +/- 7% of the left ventricle. With injection of WSLP carrier alone, 49 +/- 6% of the left ventricle was infarcted (P = NS). The constitutively expressed gene construct, SV-VEGF, reduced the infarct size to 32 +/- 7% of the left ventricle (P = 0.007). The ischemia-inducible gene construct, RTP801-VEGF, further reduced the infarct size to 13 +/- 4% of the left ventricle (P < 0.001). The use of a non-viral carrier to deliver an ischemia-inducible VEGF construct is effective in the treatment of acutely ischemic myocardium.
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