Biomedical Engineering Reference
In-Depth Information
Techniques of Gene Therapy for Restenosis
Recombinant adenoviral vectors continue to be the most efficient methods of gene
transfer into the arterial wall but concerns over the safety of using viral vectors in
a clinical situation have inspired the considerable progress that has been made in
improving both viral and nonviral modes of gene transfer. Early clinical trials have
shown that plasmid- and adenovirus-mediated vascular gene transfers can be con-
ducted safely and are well tolerated. Ex vivo gene therapy with E2F-decoy has
succeeded in reducing graft occlusion rate after surgical bypass in a randomized,
double-blind clinical trial.
An intravascular approach using a catheter is the most commonly used gene
delivery method. Various types of catheters, such as microporous gel-coated and
channel balloon catheters are available for gene transfer into vessel wall.
Adenoviruses can be prevented from being swept away by the blood stream by
double-balloon catheters but the circulation through the arteries may have to be
interrupted for longer than is considered to be safe.
The efficacy of gene transfer through atherosclerotic lesions is low. Therefore,
needle catheters have been devised that perform the injection from inside of the
vessel lumen through the atherosclerotic lesion so that the genes are delivered
directly to the vessel wall. Gene transfer vectors can also be delivered to the artery
adventitia with a biodegradable collar, biodegradable gel, or a direct injection into
the adventitia.
NOS Gene Therapy for Restenosis
Endogenous NO in the vasculature is vasoprotective by inhibiting platelet and leu-
kocyte adhesion, inhibiting SMC proliferation and migration, and promoting
endothelial survival and proliferation. At sites of vascular injury following angio-
plasty, the endothelium is disrupted and NO synthesis is impaired. Hence,
augmenting local NO synthesis through NOS gene transfer may help arrest the
proliferative response to vascular injury. Delivery of eNOS gene to balloon-injured
rat carotid arteries using HVJ-liposomes results in 70% reduction in neointimal
formation 2 weeks after balloon injury. SMCs engineered to express eNOS using
retrovirus onto the luminal surface of balloon-injured rat carotid arteries also inhibit
neointimal formation.
Other studies have similarly shown that adenoviral delivery of eNOS to balloon-
injured rat and porcine arteries can limit intimal hyperplasia. The effect of eNOS and
plasminogen activator inhibitor 1 (PAI-1) gene transfer on neointimal formation was
compared in balloon-injured porcine coronary arteries. Adenoviral-mediated eNOS,
but not PAI-1 gene transfer, could significantly inhibit the neointimal formation at
4 weeks after intramural gene delivery. No acute systemic toxicity was observed
after gene transfer. The results suggest that local gene transfer of eNOS may hold
promise as a safe and effective adjunctive treatment to prevent postangioplasty rest-
enosis. In addition to constitutive eNOS gene transfer, iNOS gene transfer has been
investigated in balloon-injured arteries. Adenoviral-mediated iNOS gene transfer to
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