Biomedical Engineering Reference
In-Depth Information
by an AAV vector prior to induction of ischemia and oxygen deprivation with no
evidence of damage. The results of this study will be verified in a large animal
model. If the findings hold, the therapy might be ready to enter a phase I clinical
trial in human patients.
Angiogenesis and Gene Therapy of Ischemic Disorders
Angiogenesis (formation of blood vessels) is fundamental to reproduction, devel-
opment, and repair. During human embryonal growth, vessels develop to deliver
adequate nourishment and oxygen from the maternal circulation. Angioblasts of
extraembryonic mesoderm give rise to primitive vascular channels and angiogene-
sis originates from these structures. In infants, angiogenesis is proportional to the
proliferation of the tissue in which it takes place and declines in childhood. In
healthy adults, the turnover of endothelial cells is extremely low and angiogenesis
essentially does not take place.
Angiogenesis is a complex multistep process involving extensive interplay
between cells, soluble factors, and extracellular matrix components. Several angio-
genic peptides have been discovered. Some stimulate vascular endothelial cells to
proliferate whereas others act indirectly by mobilizing host cells to release endothe-
lial growth factors. The activity of these angiogenic factors is counteracted by
endogenous inhibitors of angiogenesis. Angiogenesis can be triggered by various
humoral stimuli and occurs in some diseases such as retinopathy of prematurity and
hemangiomas. Endothelial proliferation within atherosclerotic plaques of coronary
arteries can lead to hemorrhage and initiate a heart attack. Angiogenesis also occurs
during vascularization of tumors. Angiogenesis is a normal component of wound
healing, and angiogenic factors can improve the healing of chronic wounds.
Angiogenesis is a target for ischemic diseases with an intention to stimulate it
whereas the aim is to suppress it in cancer. Advances in viral and nonviral vector
technology including cell-based gene transfer have continued to improve transgene
transmission and expression efficiency. An alternative strategy to the use of trans-
genes encoding angiogenic growth factors is therapy based on transcription factors
such as hypoxia-inducible factor-1a (HIF-1a) that regulate the expression of mul-
tiple angiogenic genes. Cardiovascular gene therapy with VEGF has yielded
improved perfusion and reduced ischemia in preclinical models of ischemic heart
disease (IHD). Several preclinical studies and phase I/II clinical trials have shown
the safety and therapeutic potential of gene therapy in the treatment of IHD, periph-
eral arterial disease (PAD), restenosis, and ischemic and diabetic neuropathy, point-
ing to the need for phase III clinical trials.
Unregulated VEGF-mediated angiogenesis has the potential to promote tumor
growth, accelerate diabetic proliferative retinopathy, and promote rupture of ath-
erosclerotic plaque. To be safe and effective, gene therapy with VEGF must be
regulated. To limit the risk of pathological angiogenesis, hypoxia-inducible VEGF
gene therapy systems have been devised. For example, injection of a water-soluble
lipopolymer and an erythropoietin enhancer can induce expression of VEGF in
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