Elsevier

Drug Discovery Today

Volume 12, Issues 23–24, December 2007, Pages 1040-1045
Drug Discovery Today

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Combating cardiovascular disease with angiogenic therapy

https://doi.org/10.1016/j.drudis.2007.08.018Get rights and content

For over a decade we have lived with the promise that therapeutic angiogenesis, defined as the growth of new blood vessels in tissues damaged by poor blood perfusion, would provide a lasting clinical benefit to patients suffering from cardiovascular disease, the leading cause of death in the Western world. Numerous successful protein, gene and cell-based angiogenesis studies in animals with experimentally induced ischemia have not been followed by positive efficacy data in human trials. Armed with knowledge of the shortcomings of earlier clinical studies, emerging results from more recent trials indicate that protein-based angiogenesis therapy may provide a viable treatment option for patients suffering from advanced atherosclerotic disease.

Section snippets

Physiology of angiogenesis

In established blood vessels in mature organisms, the endothelial cells remain in a quiescent, non-proliferate state until stimulation of angiogenesis occurs by stimuli including wounding, inflammation, hypoxia or ischemia. As shown in Figure 1, the formation of new vessels can be considered as the result of several processes: (i) dissolution of the matrix underlying the endothelial cell layer; (ii) migration, adhesion and proliferation of endothelial cells; (iii) formation of a new

Angiogenesis and gene therapy

The advent of gene therapy, which received considerable scientific and medical attention, quickly found its way into gene-based angiogenesis trials in humans. Numerous Phase I trials with either adenovirus vectors carrying an angiogenesis gene, or ‘naked’ plasmid DNA vectors harbouring an angiogenic gene, demonstrated the safety of these new gene-based products (see Table 1 for a listing of angiogenesis gene therapy trials and refs. 6, 19, 20, 21, 22, 23, 24). However, as these trials

Angiogenesis and cell-based therapy

Cell-based angiogenesis therapy, although highly promising, is still many years away from large-scale clinical trials. It should be stressed that the majority of cell based clinical trials now ongoing are primarily directed at patients with heart failure and are aimed at regenerating cardiac muscle tissue. In a formal sense, these cannot be considered angiogenesis trials as new cardiac muscle cells, versus coronary vascular cells, are being formed. There have been some notable successes in

Protein therapy to stimulate angiogenesis

Early clinical studies with protein-based therapeutics 1, 2, 3, 4, 5, 12, 13, 14 largely focused on the intravenous administration of a particular growth factor to stimulate angiogenesis in the affected tissue or organ. Table 1 lists a number of these earlier trials with recombinant proteins 27, 28, 29, 30, 31, 32, and it can readily be seen that most of these trials relied on an intracoronary delivery of the angiogenic protein. Most of these trials did not achieve statistically significant

VEGF growth factors and angiogenesis

The VEGF family of proteins has been shown to play a critical role in angiogenesis 16, 33, 34. The VEGF superfamily is composed of seven members, but VEGF-A is believed to be the most important contributor to the angiogenesis process [33]. At least nine subtypes of VEGF-A have been described in the literature and the subtype composed of 165 amino acids has been most extensively utilized in ongoing angiogenesis trials 6, 21, 33. VEGF is a potent endothelial cell mitogen and transmits its

Fibroblast growth factors and angiogenesis

The FGF family with its prototype members FGF-1 and FGF-2 (basic FGF) consists to date of at least 22 known members 15, 36. Most are 16–18 kDa single chain peptides and display high affinity to heparin and heparan sulfate. In general, FGFs stimulate a variety of cellular functions by binding to cell surface FGF-receptors in the presence of heparin proteoglycans. Figure 3 depicts the three dimensional structure of FGF-1 and one of the FGF receptors to which this growth factor binds 37, 38. The

The outlook for protein therapy and angiogenesis

The goal of angiogenesis therapy is to safely and efficiently recreate the natural process in our bodies whereby new blood vessels are formed to nurture and replenish tissues that have been damaged by underperfusion and ischemia. Capitalizing on lessons learned from previous clinical trials, several high profile clinical studies are now advancing in patients with severe coronary artery disease include Cardium Therapeutic's Phase III FGF-4 gene therapy study in woman, and CardioVascular

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