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BACKGROUND: Vascular Endothelial Growth Factor (VEGF) gene therapy can promote functional recovery following myocardial infarction. Unregulated expression, however, may limit the efficacy of VEGF gene therapy within the myocardium. We have developed a novel promoter which allows gene expression only under conditions of ischemia. We compared the efficacy of ischemia-inducible VEGF gene therapy to unregulated VEGF gene therapy in limiting myocardial infarct size.
METHODS: Twenty rabbits underwent ligation of the proximal circumflex coronary artery. Immediately following ligation, the peri-infarct area was injected with one of the following: a) no injection therapy (ligation only); b) a water soluble lipopolymer (WSLP) gene carrier alone; c) an unregulated, constitutively expressed, VEGF gene construct in a WSLP carrier; or d) an ischemia-inducible VEGF gene construct in a WSLP carrier (n=5/group). The rabbits were sacrificed at 4 weeks. The ratio of infarcted to non-infarcted left ventricle was measured and expressed as % of the left ventricle infarcted. The data was analyzed using paired t-tests and is presented as the mean + standard deviation.
RESULTS: Ligation alone infarcted 48 + 7 % of the left ventricle. With injection of WSLP carrier alone, 49 + 6 % of the left ventricle remained infarcted (p=ns). The unregulated VEGF gene construct reduced the infarct size to 32 + 7 % of the left ventricle (p=0.007). The ischemia-inducible VEGF gene construct further reduced the infarct size to only 13 + 4 % of the left ventricle (p<0.001).
CONCLUSIONS: Ischemia-inducible regulation improves the efficacy of VEGF gene therapy for myocardial infarction.