In vivo myocardial gene transfer: optimization and evaluation of intracoronary gene delivery in vivo.
Clinical reports suggest that intracoronary delivery of adenoviruses encoding angiogenic growth factors, or their transactivators, has a therapeutic benefit. However there has not been a systematic assessment of the transfection efficiency of this technique in vivo. In rabbits we investigated the efficiency of myocardial gene transfer following intracoronary infusion of 1 x 10(-10) -1 x 10(12) p.f.u. of adenovirus in combination with interventions to enhance transfection. In five standard short axis sections, we were barely able to detect reporter gene expression following unmodified intracoronary infusion. Efficiency was not enhanced by the exclusion of blood and the increase of intracoronary dwell time through occlusive engagement of the left coronary ostium enabled by oxygenated perfluorocarbon emulsion as viral diluent. Of the interventions and pretreatments designed to increase vascular permeability, VEGF, calcium-free viral diluent and adenosine, only the latter tended to increase efficiency. However an intervention designed to increase the myocardial transcapillary gradient, by increasing venular pressure with pulmonary artery occlusion and arteriolar pressure with occlusion of the aorta above the coronary ostia, increased transfection efficiency by two orders of magnitude. Unfortunately the clinical utility of this technique may be limited by accompanying cardiac dilation and marked elevations in intracardiac pressure.
Wright
M J
MJ
Department of Cardiology, Kings College London, St Thomas's Hospital, London, UK.
Wightman
L M
LM
Latchman
D S
DS
Marber
M S
MS
D000241:Adenosine / Q000008:administration & dosage; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D003331:Coronary Vessels; D016228:Endothelial Growth Factors / Q000008:administration & dosage; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008222:Lymphokines / Q000008:administration & dosage; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017725:Ventricular Pressure / Q000187:drug effects; D001616:beta-Galactosidase / Q000235:genetics*
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001616:beta-Galactosidase; D000241:Adenosine