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Chapter 8: CARDIOVASCULAR TISSUE MODIFICATION BY GENETIC APPROACHES GENE TRANSFER AND VASCULAR DISEASE
Gene transfer into the vasculature has been used to investigate the pathophysiology of vascular diseases and to develop novel therapies for these diseases. This field has expanded rapidly in the past decade. A number of models in the mouse, rat, rabbit, dog, and pig have been created to dissect vascular pathophysiology in peripheral, coronary, renal, pulmonary, and cerebral blood vessels. A full discussion of these animal models is beyond the scope of this chapter, and the reader is guided to pertinent reviews.54-58
Experimental Applications of ASOs INTIMAL HYPERPLASIA
Simons et al.59 reported that the administration of ASOs against c-myb applied by pluronic gel to the adventitial layer of rat carotid arteries inhibited neointimal hyperplasia in response to balloon injury. Data from Morishita et al.34 demonstrated that a single HVJ liposome-mediated administration of ASOs against proliferating cell nuclear antigen (PCNA) and cdc2 kinase inhibited neointimal lesion formation after balloon injury for at least 8 weeks after transfection. The combination of antisense cdc2 kinase and cdk2 kinase oligonucleotides also resulted in almost complete inhibition of neointima formation.35 Bennett et al.60 showed an inhibition of vascular smooth muscle cell proliferation by administration of c-myc ASOs to the adventitial surface of injured carotid arteries in a pluronic gel solution. Two other studies reported inhibition of neointima formation after application of ASOs. Delivery of antisense PCNA oligonucleotides by pluronic gel (in a rat carotid model) and of antisense c-myc oligonucleotides by direct application through a porous balloon (in a porcine coronary artery model) resulted in significant inhibition of neointimal hyperplasia.61,62
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