Gene Therapy in Critical Limb Ischemia
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authors:
1Hong H. Keo, MD, 2Alan T. Hirsch, MD, 1Iris Baumgartner, MD, 3Sigrid Nikol, MD,
2Timothy D. Henry, MD
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Abstract
Critical limb ischemia (CLI) represents the most severe stage of atherosclerotic lower extremity peripheral artery disease (PAD), and CLI prevalence is expected to increase as the population ages. The current standard of care for CLI relies on direct revascularization, either by endovascular techniques or open surgical approaches, as there are few effective medical treatments for this condition. Therapeutic angiogenesis is a novel approach to improving limb outcomes for these patients. Experimental preclinical studies and phase I/II clinical trials of therapeutic angiogenesis using gene transfer in patients with CLI unsuitable for revascularization have shown promising results. In this review, we describe the potential clinical impact of this new approach as an adjunct in our therapeutic armamentarium.
Introduction
Critical limb ischemia (CLI) represents the most advanced stage of atherosclerotic, lower extremity peripheral artery disease (PAD) and is associated with high rates of cardiovascular morbidity, mortality, and major amputation.1 The incidence of CLI is estimated to be 125,000 to 250,000 patients per year in the United States and is expected to grow as the population ages.2–5 The 1-year mortality rate of patients with CLI is 25% and may be as high as 45% in those who have undergone amputation.1,6 The current standard of care for individuals with CLI includes lower extremity revascularization, either through open peripheral surgical procedures, endovascular techniques, or lower extremity amputation (i.e., if revascularization has failed or is unfeasible).1,7
Despite advanced techniques in endovascular and surgical procedures, a considerable proportion of patients with CLI are not suitable for revascularization. Of these patients, 30% will require major amputation and 23% will die within 3 months.8
Therapeutic angiogenesis is a novel strategy under investigation for the treatment of PAD that utilizes angiogenic growth factors, genes to encode these growth factors, or stem cells to promote neovascularization, in an attempt to increase perfusion to ischemic tissues through various mechanisms of action.9 Early clinical trials of gene transfer for therapeutic angiogenesis have been promising and provide hope for CLI patients who are unsuitable candidates for revascularization.
This paper will review the impact of therapeutic angiogenesis for the treatment of patients with CLI, including the safety and efficacy data provided by those clinical trials completed to date, and will outline potential future directions for clinical research.
The Concepts Underlying Therapeutic Angiogenesis
The concept of therapeutic angiogenesis evolved from pioneering work by Folkman,10 who observed that the development and maintenance of an adequate microvascular supply is essential for the growth of neoplastic tissue. Following the early identification of angiogenic growth factors, cardiovascular investigators began testing the hypothesis that stimulating angiogenesis could improve perfusion and function in ischemic tissues independent of macrovessel manipulation.11 Therapeutic angiogenesis involves the administration of angiogenic growth factors, as recombinant protein or gene encoding for those growth factors or stem cells to augment the collateral circulation and enhance blood flow to ischemic tissues. Angiogenic protein growth factors have been utilized, but require intra-arterial delivery and have short half lives.12,13 In particular, for PAD, gene therapy has theoretical advantages of intramuscular delivery, permitting repeated administration and a more prolonged therapeutic effect.
Angiogenic growth factors can be administered using non-viral or viral-vector encoding genes. The non-viral method uses naked plasmid DNA to transfer the gene encoding the desired angiogenic protein to the ischemic tissue.
The viral delivery method uses viruses as a vector to introduce the new gene to the ischemic tissues, also referred to as transfection. The viruses most often used in angiogenic studies are adenoviruses.14 The major advantage of this method is that transfection of growth factors can be achieved with high efficiency. However, the potential downside of this method is that transfection efficiency may be limited by prior viral exposure, and repeated administration might not be efficacious, due to rapid degradation of the viral vector.15,16
Therapeutic angiogenesis and angiogenic growth factors. Therapeutic angiogenesis was first evaluated by Dr. Jeffrey Isner in a 71-year-old patient with severe PAD and great toe gangrene in 1994.17 Human plasmid phVEGF165 in a dose of 2 mg was applied to the hydrogel polymer coating of an angioplasty balloon. By inflating the balloon in the vascular lumen, plasmid DNA was transferred to the distal popliteal artery.17 Functional and angiographic parameters improved within 12 weeks, and spider angiomata and edema developed unilaterally in the affected limb, suggesting the treatment had a local angiogenic effect. Since this pioneering, experimental therapy numerous angiogenic growth factors have been developed and tested in clinical trials with demonstration of angiogenic potential.18 Table 1 provides an overview of angiogenic growth factors that have been identified to stimulate neovascularization in preclinical and clinical models. Of these, the following four have been thus far evaluated in clinical trials of patients with CLI.
1. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): Executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol 2006;47:1239–1312.
2. Dormandy J, Mahir M, Ascady G, et al. Fate of the patient with chronic leg ischemia. A review article. J Cardiovasc Surg (Torino) 1989;30:50–57.
3. Dormandy J, Heeck L, Vig S. The fate of patients with critical leg ischemia. Semin Vasc Surg 1999;12:142–147.
4. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45:S5–S67.
5. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: Results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation 2004;110:738–743.
6. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Concensus (TASC). J Vasc Surg 2000;31:S1–S296.
7. Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): Multicenter, randomized controlled trial. Lancet 2005;366:1925–1934.
8. Lepantalo M, Matzke S. Outcome of unreconstructed chronic critical leg ischaemia. Eur J Vasc Endovasc Surg 1996;11:153–157.
9. Nikol S, Baumgartner I, Van Belle E, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther 2008;16:972–978.
10. Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182–1186.
11. Takeshita S, Zheng LP, Brogi E, et al. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 1994;93:662–670.
12. 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.
13. 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.
14. Yla-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 2003;9:694–701.
15. Dor Y, Djonov V, Abramovitch R, et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 2002;21:1939–1947.
16. Baumgartner I, Chronos N, Comerota A, et al. Local gene transfer and expression following intramuscular administration of FGF-1 plasmid DNA in patients with critical limb ischemia. Mol Ther 2009;17:914–921.
17. Isner JM, Pieczek A, Schainfeld R, et al. Clinical evidence of angiogenesis following arterial gene transfer of phVEGF165 in a patient with ischemic limb. Lancet 1996;348:370–374.
18. Tongers J, Roncalli JG, Losordo DW. Therapeutic angiogenesis for critical limb ischemia: Microvascular therapies coming of age. Circulation 2008;118:9–16.
19. Henry TD, Abraham JA. Review of preclinical and clinical results with vascular endothelial growth factors for therapeutic angiogenesis. Curr Interv Cardiol Rep 2000;2:228–241.
20. Bobek V, Taltynov O, Pinterova D, Kolostova K. Gene therapy of the ischemic lower limb — Therapeutic angiogenesis. Vascul Pharmacol 2006;44:395–405.
21. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 following intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998;97:1114–1123.
22. Galzie Z, Kinsella AR, Smith JA. Fibroblast growth factors and their receptors. Biochem Cell Biol 1997;75:669–685.
23. Gerwins P, Skoldenberg E, Claesson-Welsh L. Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis. Crit Rev Oncol Hematol 2000;34:185–194.
24. Muhlhauser J, Pili R, Merrill MJ, et al. In vivo angiogenesis induced by recombinant adenovirus vectors coding either for secreted or nonsecreted forms of acidic fibroblast growth factor. Hum Gene Ther 1995;6:1457–1465.
25. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001;294:1337–1340.
26. Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science 2001;292:464–468.
27. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995;270:1230–1237.
28. Ho TK, Abraham DJ, Black CM, Baker DM. Hypoxia-inducible factor 1 in lower limb ischemia. Vascular 2006;14:321–327.
29. Aoki M, Morishita R, Taniyama Y, et al. Therapeutic angiogenesis induced by hepatocyte growth factor: Potential gene therapy for ischemic diseases. Journal theroscler Thromb 2000;7:71–76.
30. Isner JM, Baumgartner I, Rauh G, et al. Treatment of thrombangiitis obliterans (Buerger’s disease) by intramuscular gene transfer of vascular endothelial growth factor: Preliminary clinical results. J Vasc Surg 1998;28:964–975.
31. Shyu K-G, Chang H, Wang B-W, P K. Intramuscular vascular endothelial growth factor (VEGF165) gene therapy in Chinese patients with chronic critical leg ischemia. Am J Med 2003;114:85–92.
32. Kusumanto YH, van Weel V, Mulder NH, et al. Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: A double-blind randomized trial. Hum Gene Ther 2006;17:683–691.
33. 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.
34. 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.
35. Henry TD, Comerota A, Chronos N, et al. FGF-1 plasmid gene therapy for patients with critical limb ischemia: Final results. [Abstract]. J Am Coll Cardiol 2002;39:468B.
36. Henry TD, Mendelson F, Comerota A, et al. Dose and regimen effects of intramuscular NV1FGF in patients with critical limb ischemia: A randomized, double-blind, placebo-controlled study. [Abstract]. Eur Heart J 2006;27:235.
37. Matyas L, Schulte KL, Dormandy JA, et al. Arteriogenic gene therapy in patients with unreconstructable critical limb ischemia: A randomized, placebo-controlled clinical trial of adenovirus 5-delivered fibroblast growth factor-4. Hum Gene Ther 2005;16:1202–1211.
38. Rajagopalan S, Olin J, Deitcher S, et al. Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: Phase I dose-escalation experience. Circulation 2007;115:1234–1243.
39. Powell RJ, Simons M, Mendelsohn FO, et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation 2008;118:58–65.
40. A Phase II Double-Blind, Randomized, Placebo-Controlled Study to Assess the Safety and Efficacy of AMG0001 to Improve Perfusion in Critical Leg Ischemia in Subjects Who Have Peripheral Ischemic Ulcers [NCT00189540]. http://www.clinicaltrials.gov/ct2/search. Last access, February 23, 2009.
41. 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.
42. Henry TD, Goldman J, Wang YL, et al. Hepatocyte growth factor gene therapy for patients with critical limb ischemia: Results of a phase I dose-escalation trial. J Am Coll Cardiol 2009: In press.
43. 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.
44. Laitinen M, Hartikainen J, Hiltunen MO, et al. Catheter-mediated vascular endothelial growth factor gene transfer to human coronary arteries after angioplasty. Hum Gene Ther 2000;11:263–270.
45. Rissanen TT, Vajanto I, Yla-Herttuala S. Gene therapy for therapeutic angiogenesis in critically ischaemic lower limb — on the way to the clinic. Euro J Clin Invest 2001;31:651–666.
46. A Randomized Double-Blind Placebo-Controlled Parallel Group Study of the Efficacy and Safety of XRP0038/NV1FGF on Amputation or Any Death in Critical Limb Ischemia Patients With Skin Lesions [NCT00566657]. http://www.clinicaltrials.gov/ct2/search. Last access, 02.23.2009.
47. Sprengers RW, Lips DJ, Moll FL, Verhaar MC. Progenitor cell therapy in patients with critical limb ischemia without surgical options. Ann Surg 2008;247:411–420.
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