Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor 121

Background. Adenovirus (Ad) vector-mediated gene therapy strategies have em erged as promising modalities for the "biological revascularization" of tis sues. We hypothesized that direct intramyocardial, as opposed to intracoron ary, administration of an Ad vector coding for the vascular endothelial gro wth factor 121 cDNA (Ad(GV)VEGF121.10) would provide highly focal Ad genome levels, and increases in VEGF, ideal for inducing localized therapeutic an giogenesis. Methods. Persistence and regional distribution of the vector were assessed by TaqMan real-time quantitative polymerase chain reaction technology and e nzyme-linked immunosorbent assay, after intramyocardial Ad(GV)VEGF121.10 in the rat, and either intramyocardial or intracoronary (circumflex territory ) vector in Yorkshire swine. Based on these results, we assessed the focal nature of the improved cardiac blood flow in a previously reported porcine myocardial ischemia model. Results. Intramyocardial delivery of Ad(GV)VEGF121.10 in the rat resulted i n local persistence of the Ad genome that decreased 1,000-fold over 3 weeks , with peak myo-cardial VEGF expression 24 to 72 h after vector delivery. A fter intramyocardial Ad(GV)VEGF121.10 in the circumflex distribution of pig s, Ad vector genome and VEGF protein levels were more than 1,000-fold and m ore than 90-fold higher, respectively, in this distribution than in other m yocardial regions. In comparison, intracoronary injection yielded maximum m yocardial Ad genome and VEGF levels 33-fold and 9-fold lower, respectively, than that after intramyocardial delivery. Angiograms obtained 28 days afte r intramyocardial Ad(GV)VEGF121.10 demonstrated rapid circumflex reconstitu tion via collaterals localized to the region of vector administration. Conclusions. These studies demonstrate that direct intramyocardial administ ration of Ad(VG)VEGF121.10 results in focal genome and VEGF levels, includi ng focal angiogenesis, sufficient to normalize blood flow to the ischemic m yocardium, findings that are relevant to designing human trials of gene the rapy-mediated cardiac angio genesis. (C) 2000 by The Society of Thoracic Su rgeons.