Gene Therapy for Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 235

of atherosclerosis. Platelet derived growth factor (PDGF), fibroblast growth factor
(FGF), and tumor growth factor (TGF-b) are also believed to be involved in the
inflammatory response in atherosclerosis. Use of antisense genes against these
factors offers another possibility of prevention of cardiovascular disease.
Myocardial infarction and subsequent reperfusion lead to the activation of apop-
tosis, and the final destruction of the cell. An experimental approach to management
of myocardial infarction is to transfer genes that stop programmed cell death or
apoptosis and promote the regeneration of new cells. Inhibition of caspases, the main
executioners of apoptosis, improves functional outcome after ischemia and reperfu-
sion in animal models. Adenoviral gene transfer of the caspase inhibitor p35 leads
to a significant reduction of the myocardial infarct size after ischemia and reperfu-
sion as well significant improvement of hemodynamic variables (Bott-Flugel et al.
2005 ). Targeted inhibition of apoptosis in the myocardium appears to be a promising
approach for ameliorating the effects of ischemia and reperfusion. Although genes
to promote these functions can be transferred to cardiac muscle cells in animals
using adenoviral vectors, clinical applications of this are some years away.
Another aim of gene therapy is to counteract the cellular toxic effects of blood
components that are known to participate at sites of thrombosis and hemorrhage.
Overexpression of heme oxygenase (HO), a stress protein that participates in
defense mechanisms against such oxidative injury, has been demonstrated by trans-
fection of HO gene into rabbit microvessel endothelial cells.
Angiogenesis for Cardiovascular Disease
Angiogenesis represents an excellent therapeutic target for the treatment of cardio-
vascular disease. It is a physiological process that underlies the manner in which
the body responds to impairment of blood supply to vital organs, that is, the produc-
tion of new collateral vessels to overcome the ischemic insult. A large number of
preclinical studies have been performed with protein, gene, and cell-based therapies
in animal models of cardiac ischemia as well as models of peripheral artery disease.
Various agents including growth factors have been tested for this purpose but there
is no effective proven therapy. Although transplantation of mononuclear cells
(MNCs) induces angiogenesis in MI, transplantation requires a large amount of
bone marrow or peripheral blood cells. Retrograde transplantation of peripheral
blood MNCs expressing hVEGF efficiently induces angiogenesis and improves the
impaired left ventricle function in hearts of pigs with AMI (Hagikura et al. 2010 ).
These findings indicate that angiogenic cells and gene therapy may be useful to
treat ischemic heart disease.
Several gene therapy angiogenesis trials have been conducted in humans.
Numerous phase I trials with either adenovirus vectors carrying an angiogenesis
gene, or naked plasmid DNA vectors harboring an angiogenic gene, have demon-
strated the safety of these new gene-based products. Fibroblast growth factor (FGF)
has shown promise for this indication (Jacobs 2007 ). Several clinical trials are now
advancing in patients with severe CHD including Cardium Therapeutic's phase III
FGF-4 gene therapy study in woman.