Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct |
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Authors: | Yockman J W Choi D Whitten M G Chang C W Kastenmeier A Erickson H Albanil A Lee M Kim S W Bull D A |
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Affiliation: | Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah Health Sciences Center, Salt Lake City, UT, USA. |
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Abstract: | 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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