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 emerged as promising modalities for the "biological revascularization" of tissues. We hypothesized that direct intramyocardial, as opposed to intracoronary, administration of an Ad vector coding for the vascular endothelial growth factor 121 cDNA (Ad(GV)VEGF121.10) would provide highly focal Ad genome levels, and increases in VEGF, ideal for inducing localized therapeutic angiogenesis.


METHODS
Persistence and regional distribution of the vector were assessed by TaqMan real-time quantitative polymerase chain reaction technology and enzyme-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 in local persistence of the Ad genome that decreased 1,000-fold over 3 weeks, with peak myocardial VEGF expression 24 to 72 h after vector delivery. After intramyocardial Ad(GV)VEGF121.10 in the circumflex distribution of pigs, Ad vector genome and VEGF protein levels were more than 1,000-fold and more than 90-fold higher, respectively, in this distribution than in other myocardial regions. In comparison, intracoronary injection yielded maximum myocardial Ad genome and VEGF levels 33-fold and 9-fold lower, respectively, than that after intramyocardial delivery. Angiograms obtained 28 days after intramyocardial Ad(GV)VEGF121.10 demonstrated rapid circumflex reconstitution via collaterals localized to the region of vector administration.


CONCLUSIONS
These studies demonstrate that direct intramyocardial administration of Ad(GV)VEGF121.10 results in focal genome and VEGF levels, including focal angiogenesis, sufficient to normalize blood flow to the ischemic myocardium, findings that are relevant to designing human trials of gene therapy-mediated cardiac angiogenesis.
Lee
L Y
LY
Department of Cardiothoracic Surgery, The New York Hospital-Cornell Medical Center, New York, USA.
Patel
S R
SR
Hackett
N R
NR
Mack
C A
CA
Polce
D R
DR
El-Sawy
T
T
Hachamovitch
R
R
Zanzonico
P
P
Sanborn
T A
TA
Parikh
M
M
Isom
O W
OW
Crystal
R G
RG
Rosengart
T K
TK
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003097:Collateral Circulation / Q000235:genetics; D017023:Coronary Angiography; D003326:Coronary Circulation / Q000235:genetics / Q000502:physiology; D003331:Coronary Vessels; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors; D016679:Genome, Viral; D006801:Humans; D008222:Lymphokines / Q000032:analysis / Q000235:genetics*; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium; D018919:Neovascularization, Physiologic / Q000235:genetics*; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors