Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 292

nitric oxide bioavailability and increasing superoxide levels [205,206] . Studies using
adenoviral vectors revealed that the overexpression of the eNOS gene in hyperten-
sion rat models resulted in restoration of normal function of the vascular endothelium
[207,208] . Like eNOS overexpression in rat models, the overexpression of EC-SOD
resulted in a significant reduction in hypertension in the rat model [209,210] .
6.5.2 Hypercholesterolemia and Atherosclerosis
Defects in the low-density lipoprotein receptors (LDLR) are the primary cause of
familial hypercholesterolemia, an inherited disorder. The diseased patients show high
blood low-density lipoprotein (LDL) levels, leading to coronary artery disease, periph-
eral vascular diseases, and accelerated atherosclerosis [195,211] . The various targets
for gene therapy in hypercholesterolemia and atherosclerosis include LDL receptors,
VLDL receptors, apoproteins A and E, lipoprotein lipase, hepatic lipase, and so on.
LDL and VLDL receptors, especially in liver and muscles, are the prime targets
for gene therapy trials of hypercholesterolemia in various animal models. For exam-
ple, ex vivo gene transfer of the LDL gene in familial hypercholesterolaemia [212] , in
vivo delivery of the LDL receptor gene using recombinant adenoviruses and retrovi-
rus in the watanabe heritable hyperlipidemic rabbit model [213,214] , and adenovirus-
mediated VLDL receptor gene delivery in the mouse model [215] have shown prom-
ising results in hyperlipidemic conditions. Gene therapy trials using hepatic lipase
showed promising results in lowering the level of lipoproteins in hyperlipedemia, using
adenoviral vectors in rat and rabbit animal models [216,217] . A number of gene therapy
trials using different vectors have been carried out for lowering the high concentration
of apolipoproteins in atherosclerosis. For example, overexpression of human lipopro-
tein lipase gene using adenoviral vectors resulted in a decreased level of lipoproteins,
ameliorating the hyperlipidemias [218,219] . Atherogenic apolipoprotein (a) inhibition
using ribozyme oligonucleotides was also used as a novel strategy for atherosclerosis
[220] . The transfer of apoprotein A-I, a principal protein of HDL, also improved the
circulating high-density lipoprotein cholesterol in the mice model [221,222] .
6.5.3 Thrombosis
Thrombosis or clot formation in blood vessels occurs due to many reasons, for exam-
ple, endothelial wall dysfunction, resulting in the reduction of normal antithrombotic
activity. The experimental gene therapy for thrombosis involves the transfer of genes
encoding for antiplatelet factors and anticoagulation factors. The various anticoagu-
lant factors that have been used in gene therapy to prevent thrombosis of blood ves-
sels are hirudin, thrombomodulin, antistasin, tissue plasminogen activator (tPA), and
tissue factor pathway inhibitor (TFPI) [223] .
One study demonstrated that adenovirus-mediated expression of recombinant
hirudin locally resulted in reduced neointima formation after arterial injury [224] .
Another study in the rabbit model showed that local overexpression of tPA prevented
arterial thrombosis [225] . Moreover, the adenovirus-mediated local delivery of TFPI
showed promising results in the inhibition of thrombus in rabbit and porcine carotid