Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 293

artery models [226,227] . A rabbit stasis injury model of arterial thrombosis, local
overexpression of thrombomodulin, using adenovirus, resulted in the reduction
of thrombosis, without any inflammatory damage to the vector at the site of deliv-
ery [228] . A strategy has also been designed to deliver antiplatelet genes to prevent
thrombosis in experimental models. A study showed that adenovirus-mediated local
overexpression of cyclo-oxygenase-1 (COX-1) to porcine carotid arteries resulted in
the inhibition of thrombosis in injured vessels [229] .
6.5.4 Ischemia
Ischemia is characterized by impaired blood supply to the tissues. Peripheral isch-
emia may result from many clinical reasons such as narrowed, blocked, or clotted
arteries, which subsequently starve tissues of the necessary nutrients and oxygen.
Myocardial ischemia results from improper blood supply to the heart. This may occur
if coronary flow is reduced by the presence of an atherosclerotic plaque, a blood clot,
or an artery spasm. Gene therapy can provide an exciting alternative approach for
ischemic tissues, to restore the normal blood supply [230] .
Therapeutic angiogenesis to increase the number of small blood vessels in tis-
sues is one of the most frequently used gene therapy approaches in ischemia. The
vascular endothelial growth factor family (VEGF-A, B, C, D, E) is one of the most
frequently used to target therapeutic angiogenesis. The naked plasmid encoding for
VEGF improved the tissue perfusion, using intramuscular injection [231] . Moreover,
Ad-mediated delivery of VEGF cDNA improved myocardial perfusion and func-
tion in the ischemic porcine heart [232] . VEGF protein also showed revasculariza-
tion and improved blood flow in rabbit and dog models [233,234] . The intramuscular
injection of Ad/VEGF121 resulted in significant lengthening of arterioles and capil-
laries of nonischemic limbs in the rat and rabbit [235] . In clinical studies also, the
Ad-mediated VEGF121 improved the endothelial function in patients with peripheral
arterial disease, and myocardial injection into the ischemic region improved the car-
diac functions [236,237] .
The fibroblast growth factor family (FGFs) is another important target for angio-
genesis induction. For example, intracoronary gene transfer of FGF-5 resulted in
increased blood flow and contractile function in an ischemic heart [238] . Moreover,
FGF-2 showed angiogenic potential in the porcine model of chronic myocardial isch-
emia [239] .
6.5.5 Gene Therapy for Graft Failures
When vein grafts are inserted into the circulation, they undergo a sequence of adap-
tive physiological changes. Early thrombosis occurs in the first few weeks after graft-
ing, particularly at the distal anastomosis, due to vessel wall injury. Late vein graft
failure is characterized by progressive medial thickening and neointima formation.
Therefore, vein graft failure limits the clinical success of coronary bypass grafting
in terms of symptoms and mortality. Generally, antiplatelet drugs like aspirin reduce
the incidence of acute thrombosis in bypass grafts, but long-term efficacy of these