Biomedical Engineering Reference
In-Depth Information
the time of angioplasty in animal models has been shown to be sufficient to inhibit
vascular SMC proliferation and neointimal formation significantly.
P21 and possibly related cyclin-dependent kinase inhibitors may normally regu-
late cellular proliferation following arterial injury, and strategies to increase its
expression may prove therapeutically beneficial in vascular diseases. P21 is a
downstream target of the p53 tumor suppressor gene and has been implicated in
abnormalities of cell proliferation. Expression of p21 directly inhibits the kinase
activities of cyclin/CDK complexes in vitro. P21 also inhibits proliferating cell
nuclear antigen (PCNA)-dependent DNA replication but not DNA repair in vitro.
Localized arterial infection with a p21-encoding adenovirus at the time of balloon
angioplasty significantly reduces neonatal intimal hyperplasia in the rat carotid
artery model of restenosis. Direct gene transfer of p21 using adenoviral vector into
balloon-injured porcine arteries inhibits development of intimal hyperplasia.
Another potential strategy is adenoviral-mediated delivery of gene encoding
herpes simplex thymidine kinase (HSV-tk). When HSV-tk is expressed in human
cells, cell proliferation can be inhibited by exposure of the cells to ganciclovir,
a nucleoside analogue. HSV-tk phosphorylates ganciclovir forms a nucleotide
analog, which is incorporated into the elongating DNA strand, and inhibits further
DNA synthesis. Adenoviral-mediated transfer and expression of HSV-tk in balloon-
injured femoral artery of hyperlipidemic rabbit results in reduction in intimal pro-
liferation. Inhibition of cell proliferation in atherosclerotic arteries constitutes a
possible treatment for vascular proliferative disease in human patients.
Interferon gamma (IFN-g), a product of T lymphocytes, found in atherosclerotic
lesions, inhibits smooth muscle cell proliferation in vitro. Transfer and expression
of the IFN-g gene in human endothelial cells has been shown to inhibit vascular
smooth muscle cell growth in vitro. This may be a useful therapy for restenosis
after angioplasty.
The gax (growth arrest-specific homeobox) is a potentially important gene in the
process of smooth muscle cell differentiation. That gax is important for the devel-
opment of restenosis has been demonstrated in animal models of balloon injury
where expression of gax is rapidly downregulated as cell proliferation increases.
Investigations are in progress to determine the effect of increasing expression of
gax in animal models by gene therapy. This may have potential applications in
management of restenosis.
Pharmacokinetics of adenoviral-mediated gene delivery to the vascular smooth
muscle cells can be modulated by agents such as polaxamer 407 (a viscous biocom-
patible polyol), which may improve gene delivery by maintaining pericellular
concentrations of vector. This technique may allow desired levels of gene transfer
with lower total viral dose and exposure time. Because of the multiplicity of the
factors involved in restenosis, a cocktail of genes that affect different aspects of
restenosis may have to be used. The adenovirus-encoded ribozyme to PDGF
A-chain mRNA has been shown to inhibit neointimal formation in a rat carotid
artery injury model and this may serve as a novel strategy to prevent restenosis after
coronary angioplasty.
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