Circulation, Vol 90, 2402-2413, Copyright © 1994 by American Heart Association
BA French, W Mazur, NM Ali, RS Geske, JP Finnigan, GP Rodgers, R Roberts and AE Raizner
BACKGROUND--Gene therapy has been proposed as a possible solution to the
problem of restenosis after coronary angioplasty. The current study was
undertaken to assess conventional methods of gene transfer and to develop
percutaneous techniques for introducing genes directly into the coronary
arteries of large mammals. Since the anticipated targets of gene therapy
against restenosis include atherosclerotic and previously instrumented
arteries, we also evaluated gene transfer in atherosclerotic coronary
arteries and in two porcine models of restenosis: one using intracoronary
stents and a second using balloon overstretch angioplasty. METHODS AND
RESULTS--The conventional method of using perforated balloon catheters to
deliver Lipofectin-DNA complexes directly into the coronary arteries of
intact animals was applied to 18 porcine coronary arteries including normal
arteries, hypercholesterolemic arteries, and those simulating restenosis.
The results of this study were consistent with previously published results
indicating that only low levels of luciferase gene expression could be
obtained by Lipofectin-mediated gene transfer. We therefore undertook a
second, parallel study to evaluate percutaneous transluminal in vivo gene
transfer using a replication-deficient adenoviral vector. A comparison of
the two studies revealed that the mean level of reporter gene expression in
the cohort undergoing adenoviral infection was 100- fold higher than in the
cohort undergoing Lipofection. Analysis of luciferase activity over time in
normal arteries revealed that recombinant gene expression was half-maximal
after 1 day, peaked within 1 week, was still half-maximal at 2 weeks, and
declined to low levels by 4 weeks. Histochemical analysis of coronary
arteries treated with a second adenovirus expressing a nuclear-localized
beta-galactosidase gene demonstrated gene transfer to a limited number of
cells in the media and adventitia. Immunohistochemical analysis of
Ad5-infused arteries using a monoclonal antibody directed against CD44
identified a periadventitial infiltrate composed of leukocytes.
CONCLUSIONS--The recombinant adenoviral vectors proved to be far more
effective than Lipofectin at delivering foreign genes directly into the
coronary arteries of living mammals. Furthermore, the influences of
hypercholesterolemia and arterial injury appeared to have little effect on
the levels of gene expression obtained using either method. The results
demonstrate that low-level recombinant gene expression, the major obstacle
impeding gene therapy for the prevention of restenosis, can potentially be
overcome by using adenoviral vectors to mediate coronary gene transfer in
vivo. The duration of gene expression provided by these vectors and their
effective deployment in atherosclerotic, balloon-overstretched, and stented
coronary arteries suggest that recombinant adenovirus may have potential
for evaluating gene therapy in the clinically informative porcine models of
coronary restenosis.
ARTICLES
Percutaneous transluminal in vivo gene transfer by recombinant adenovirus in normal porcine coronary arteries, atherosclerotic arteries, and two models of coronary restenosis
Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
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