Therapeutic Angiogenesis for the Treatment of PAD – Where Do We Stand?
- Fri, 9/5/08 - 3:36pm
- 0 Comments
- 4202 reads
Introduction
The prevalence of peripheral arterial disease (PAD) in the adult population is as high as 12–18%.1,2 Conservative treatments, including risk factor modification, supervised exercise training and medical therapy are indicated in patients whose lower extremity PAD has not reached an advanced stage. Symptoms of intermittent claudication may improve with these maneuvers.3 However, pharmacologic treatments have had limited impact on the outcome of lower extremity PAD when the disease progresses to a state of critical limb ischemia (CLI). Percutaneous transluminal angioplasty (PTA) and reconstructive arterial surgery have their known limitations, with high restenosis and graft failure rates, especially in infra-popliteal disease. Hence, induction of therapeutic angiogenesis has been attempted in patients with advanced PAD in order to establish a safe method of revascularization that ensures stable, viable and durable vasculature. Most of the information about therapeutic angiogenesis in cardiovascular disease has been gained from its application in coronary heart disease, with significantly less information available on the treatment of PAD.4,5 This review summarizes current clinical data on patients with PAD who underwent therapeutic angiogenesis in the context of phase I and phase II clinical trials.
Angiogenesis
The term, “angiogenesis,” used liberally in the cardiovascular community, refers to any form of new vessel growth. However, it is useful to distinguish between three different aspects of neovascularization: angiogenesis, arteriogenesis and vasculogenesis. Angiogenesis in its strictest definition describes capillary growth from enlarged venules, and is mainly stimulated by tissue hypoxia involving several mediators, including hypoxia-inducible factor (HIF)-1 alpha, vascular endothelial growth factor (VEGF) and angiopoietin-2.6,7 Arteriogenesis is a process that produces fully developed arteries which, in contrast to angiogenesis, is usually large enough to be visualized with angiography.8,9 Among the factors involved in this process are fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and VEGF. Finally, vasculogenesis is the formation of new vessels from endothelial and vascular progenitor cells, as seen in embryonic development. For the purpose of this review, therapeutic angiogenesis refers to the formation of both capillary structures and arterial conduits unless otherwise noted.
Potential Candidate Genes
Different classes of gene products involved in the physiologic process of angiogenesis are potential candidates for gene therapy. These include growth factors, transcription factors, certain chemokines and extracellular matrix proteins. VEGF and FGF are the best characterized angiogenic growth factors. The VEGF family is comprised of five closely related genes: VEGF-A to –D and PDGF.10,11 VEGF-A has several isoforms that differ by their amino acid length, of which VEGF-A121 and VEGF-A165 are most widely studied in clinical trials. Of the 23 different FGF family members, FGF-1, FGF-2 and FGF-4 are highly angiogenic and thus have also been studied in several clinical trials.12 Physiologically, VEGF and FGF are involved in the process of arteriogenesis, the de novo formation of true arterial conduits, but only VEGF appears to be an important factor in angiogenesis, according to its strictest definition.6,13 HIF-1 alpha activates the transcription of several genes involved in the latter process, including VGEF and inducible nitric oxide synthase (iNOS), and consequently represents another possible target for gene therapy.14 Hepatocyte-growth factor (HGF) represents another potential candidate gene for therapeutic angiogenesis, which has proven to be a potent angiogenic growth factor.15 PR39, a peptide regulator for angiogenesis which upregulates HIF-1 alpha, the chemokine monocyte chemoattractant protein-1 (MCP-1), or extracellular matrix proteins such as Cyr61 are further potential candidates, all of which have not yet been evaluated in humans.13,16,17
Product Formulation and Delivery
There are three factors to be considered in therapeutic angiogenesis: the purified protein versus gene delivery (DNA); the vector for delivery; and the route of delivery, which can be transcatheter/intra-arterial, systemic/intravenous, or application by direct intramuscular injection in the ischemic limb region. The advantages of protein formulations include predictable pharmacokinetics and tissue therapeutic levels, but the short half-life of these proteins limits the duration of exposure. Most of the earliest therapeutic angiogenesis studies employed recombinant formulations of angiogenic growth factors. Following discouraging results, a shift occurred towards gene transfer. Several advantages apply to the concept of gene transfer over the usage of recombinant proteins, including a more prolonged expression of the angiogenic factor. However, low level gene expression, induction of an inflammatory response and absence of regulation of gene expression have been significant limiting factors of this technique.18,19
1. Criqui MH, Fronek A, Barrett-Connor E, et al. The prevalence of peripheral arterial disease in a defined population. Circulation 1985;71:510–515.
2. Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: Cross-sectional study. Atherosclerosis 2004;172:95–105.
3. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med 2001;344:1608–1621.
4. Fam NP, Verma S, Kutryk M, Stewart DJ. Clinician guide to angiogenesis. Circulation 2003;108:2613–2318.
5. Fukuda S, Yoshii S, Kaga S, et al. Angiogenic strategy for human ischemic heart disease: Brief overview. Mol Cell Biochem 2004;264:143–149.
6. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: Role of the HIF system. Nat Med 2003;9:677–684.
7. Carmeliet P. Angiogenesis in health and disease. Nat Med 2003;9:653–660.
8. Helisch A, Schaper W. Arteriogenesis: The development and growth of collateral arteries. Microcirculation 2003;10:83–97.
9. de Muinck ED, Simons M. Re-evaluating therapeutic neovascularization. J Mol Cell Cardiol 2004;36:25–32.
10. Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407:242–248.
11. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–676.
12. Horowitz A, Tkachenko E, Simons M. Fibroblast growth factor-specific modulation of cellular response by syndecan-4. J Cell Biol 2002;157:715–725.
13. Schaper W, Scholz D. Factors regulating arteriogenesis. Arterioscler Thromb Vasc Biol 2003;23:1143–1151.
14. Guillemin K, Krasnow MA. The hypoxic response: Huffing and HIFing. Cell 1997;89:9–12.
15. Morishita R, Nakamura S, Hayashi S, et al. Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 1999;33:1379–1384.
16. Li J, Post M, Volk R, et al. PR39, a peptide regulator of angiogenesis. Nat Med 2000;6:49–55.
17. Babic AM, Kireeva ML, Kolesnikova TV, Lau LF. CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci USA 1998;95:6355–6360.
18. Laham RJ, Simons M, Sellke F. Gene transfer for angiogenesis in coronary artery disease. Annu Rev Med 2001;52:485–502.
19. Laham RJ, Mannam A, Post MJ, Sellke F. Gene transfer to induce angiogenesis in myocardial and limb ischaemia. Expert Opin Biol Ther 2001;1:985–994.
20. Yla-Herttuala S, Martin JF. Cardiovascular gene therapy. Lancet 2000;355:213–222.
21. Kootstra NA, Verma IM. Gene therapy with viral vectors. Annu Rev Pharmacol Toxicol 2003;43:413–439.
22. Laitinen M, Pakkanen T, Donetti E, et al. Gene transfer into the carotid artery using an adventitial collar: Comparison of the effectiveness of the plasmid-liposome complexes, retroviruses, pseudotyped retroviruses, and adenoviruses. Hum Gene Ther 1997;8:1645–1650.
23. Norman J, Denham W, Denham D, et al. Liposome-mediated, nonviral gene transfer induces a systemic inflammatory response which can exacerbate pre-existing inflammation. Gene Ther 2000;7:1425–1430.
24. Powell C, Shansky J, Del TM, Vandenburgh HH. Bioartificial muscles in gene therapy. Methods Mol Med 2002;69:219–231.
25. Laitinen M, Makinen K, Manninen H, et al. Adenovirus-mediated gene transfer to lower limb artery of patients with chronic critical leg ischemia. Hum Gene Ther 1998;9:1481–1486.
26. Rajagopalan S, Mohler E, III, Lederman RJ, et al. Regional Angiogenesis with Vascular Endothelial Growth Factor (VEGF) in peripheral arterial disease: Design of the RAVE trial. Am Heart J 2003; 145:1114–1118.
27. Arras M, Mollnau H, Strasser R, et al. The delivery of angiogenic factors to the heart by microsphere therapy. Nat Biotechnol 1998;16:159–162.
28. Villanueva FS, Jankowski RJ, Klibanov S, et al. Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation 1998;98:1–5.
29. Isner JM, Pieczek A, Schainfeld R, et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 1996;348:370–374.
30. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998;97:1114–1123.
31. Rajagopalan S, Trachtenberg J, Mohler E, et al. Phase I study of direct administration of a replication deficient adenovirus vector containing the vascular endothelial growth factor cDNA (CI-1023) to patients with claudication. Am J Cardiol 2002;90:512–516.
32. Comerota AJ, Throm RC, Miller KA, et al. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: Preliminary results of a phase I trial. J Vasc Surg 2002;35:930–936.
33. Mohler ER, III, Rajagopalan S, Olin JW, et al. Adenoviral-mediated gene transfer of vascular endothelial growth factor in critical limb ischemia: Safety results from a phase I trial. Vasc Med 2003; 8:9–13.
34. Shyu KG, Chang H, Wang BW, Kuan P. Intramuscular vascular endothelial growth factor gene therapy in patients with chronic critical leg ischemia. Am J Med 2003;114:85–92.
35. Lazarous DF, Unger EF, Epstein SE, et al. Basic fibroblast growth factor in patients with intermittent claudication: Results of a phase I trial. J Am Coll Cardiol 2000;36:1239–1244.
36. Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports dealing with lower extremity ischemia: Revised version. J Vasc Surg 1997;26:517–538.
37. Morishita R, Aoki M, Hashiya N, et al. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension 2004;44:203–209.
38. Lederman RJ, Mendelsohn FO, Anderson RD, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): A randomised trial. Lancet 2002;359:2053–2058.
39. Cooper LT, Jr., Hiatt WR, Creager MA, et al. Proteinuria in a placebo-controlled study of basic fibroblast growth factor for intermittent claudication. Vasc Med 2001;6:235–239.
40. Rajagopalan S, Mohler ER, III, Lederman RJ, et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: A phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 2003;108:1933–1938.
41. Makinen K, Manninen H, Hedman M, et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: A randomized, placebo-controlled, double-blinded phase II study. Mol Ther 2002;6:127–133.
42. Pislaru S, Janssens SP, Gersh BJ, Simari RD. Defining gene transfer before expecting gene therapy: Putting the horse before the cart. Circulation 2002;106:631–616.
43. Hertzer NR, Beven EG, Young JR, et al. Coronary artery disease in peripheral vascular patients. A classification of 1000 coronary angiograms and results of surgical management. Ann Surg 1984;199:223–233.
44. Barger AC, Beeuwkes R, III, Lainey LL, Silverman KJ. Hypothesis: Vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 1984;310:175–177.
45. Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182–1186.
46. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–1487.
47. Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983–985.
48. Baumgartner I, Rauh G, Pieczek A, et al. Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor. Ann Intern Med 2000;132:880–884.
49. van der ZR, Murohara T, Luo Z, et al. Vascular endothelial growth factor/vascular permeability factor augments nitric oxide release from quiescent rabbit and human vascular endothelium. Circulation 1997;95:1030–1037.
50. Cuevas P, Carceller F, Ortega S, Zazo M, Nieto I, Gimenez-Gallego G. Hypotensive activity of fibroblast growth factor. Science 1991;254:1208–1210.
51. Rajagopalan S, Olin JW, Young S, et al. Design of the Del-1 for therapeutic angiogenesis trial (DELTA-1), a phase II multicenter, double-blind, placebo-controlled trial of VLTS-589 in subjects with intermittent claudication secondary to peripheral arterial disease. Hum Gene Ther 2004;15:619–624.
52. Paul SA, Simons JW, Mabjeesh NJ. HIF at the crossroads between ischemia and carcinogenesis. J Cell Physiol 2004;200:20–30.
53. Rajagopalan S, Deitcher S, Olin J, et al. Harnessing the response to hypoxia: Use of a constitutively active hypoxia-inducible factor 1-alpha transgene in no-option critical limb ischemia patients. Circulation 2003;108 (Suppl. IV):IV–442 (abstract).
54. Justicz AG, Farnsworth WV, Soberman MS, et al. Reduction of myocardial infarct size by poloxamer 188 and mannitol in a canine model. Am Heart J 1991;122:671–680.
55. Schaer GL, Hursey TL, Abrahams SL, et al. Reduction in reperfusion-induced myocardial necrosis in dogs by RheothRx injection (poloxamer 188 N.F.), a hemorheological agent that alters neutrophil function. Circulation 1994;90:2964–2675.
Post new comment