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Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia

Gene Therapy volume 10, pages 285–291 (2003)Cite this article

Abstract

After extensive investigation in preclinical studies and recent clinical trials, gene therapy has been established as a potential method to induce therapeutic angiogenesis in ischemic myocardial and limb disease. Advancements in viral and nonviral vector technology including cell-based gene transfer will continue to improve transgene transmission and expression efficiency. An alternative strategy to the use of transgenes encoding angiogenic growth factors is therapy based on transcription factors such as hypoxia-inducible factor-1α (HIF-1α) that regulate the expression of multiple angiogenic genes. Further understanding of the underlying biology of neovascularization is needed to determine the ability of growth factors to induce functionally significant angiogenesis in patients with atherosclerotic disease and associated comorbid conditions including endothelial dysfunction, which may inhibit blood vessel growth. The safety and tolerability of therapeutic angiogenesis by gene transfer has been demonstrated in phase I clinical trials. However, limited evidence of efficacy resulted from early phase II studies of angiogenic gene therapy for ischemic myocardial and limb disease. The utility of therapeutic angiogenesis by gene transfer as a treatment option for ischemic cardiovascular disease will be determined by adequately powered, randomized, placebo-controlled phase II and III clinical trials.

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References

  1. Laham R, Simons M . Growth factor therapy in ischemic heart disease. In: Rubanyi G (ed). Angiogenesis in Health and Disease. Marcel Decker: New York, 2000, pp 451–475.

    Google Scholar 

  2. Carmeliet P . Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6: 389–395.

    Article  CAS  Google Scholar 

  3. Laham RJ, Simons M, Sellke F . Gene transfer for angiogenesis in coronary artery disease. Annu Rev Med 2001; 52: 485–502.

    Article  CAS  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. Simons M et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation 2000; 102: E73–E86.

    Article  CAS  Google Scholar 

  6. Qian HS et al. Improved adenoviral vector for vascular gene therapy: beneficial effects on vascular function and inflammation. Circ Res 2001; 88: 911–917.

    Article  CAS  Google Scholar 

  7. Maione D et al. An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus. Proc Natl Acad Sci USA 2001; 98: 5986–5991.

    Article  CAS  Google Scholar 

  8. Hofman CR et al. Efficient in vivo gene transfer by PCR amplified fragment with reduced inflammatory activity. Gene Therapy 2001; 8: 71–74.

    Article  CAS  Google Scholar 

  9. Norman J et al. Liposome-mediated, nonviral gene transfer induces a systemic inflammatory response which can exacerbate pre-existing inflammation. Gene Therapy 2000; 7: 1425–1430.

    Article  CAS  Google Scholar 

  10. Lawrie A et al. Microbubble-enhanced ultrasound for vascular gene delivery. Gene Therapy 2000; 7: 2023–2027.

    Article  CAS  Google Scholar 

  11. Taniyama Y et al. Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle. Gene Therapy 2002; 9: 372–380.

    Article  CAS  Google Scholar 

  12. Taniyama Y et al. Local delivery of plasmid DNA into rat carotid artery using ultrasound. Circulation 2002; 105: 1233–1239.

    Article  CAS  Google Scholar 

  13. Simberg D et al. Phase behavior, DNA ordering, and size instability of cationic lipoplexes. Relevance to optimal transfection activity. J Biol Chem 2001; 276: 47453–47459.

    Article  CAS  Google Scholar 

  14. Gowdak LH et al. Induction of angiogenesis by cationic lipid-mediated VEGF165 gene transfer in the rabbit ischemic hindlimb model. J Vasc Surg 2000; 32: 343–352.

    Article  CAS  Google Scholar 

  15. Aoki M et al. Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets. Gene Therapy 2000; 7: 417–427.

    Article  CAS  Google Scholar 

  16. Powell C, Shansky J, Del Tatto M, Vandenburgh HH . Bioartificial muscles in gene therapy. Methods Mol Med 2002; 69: 219–231.

    PubMed  Google Scholar 

  17. Lu Y et al. Recombinant vascular endothelial growth factor secreted from tissue-engineered bioartificial muscles promotes localized angiogenesis. Circulation 2001; 104: 594–599.

    Article  CAS  Google Scholar 

  18. Suzuki K et al. Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts. Circulation 2001; 104: I207–I212.

    Article  CAS  Google Scholar 

  19. Iwaguro H et al. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 2002; 105: 732–738.

    Article  CAS  Google Scholar 

  20. Khan TA, Sellke FW, Laham RJ . Therapeutic angiogenesis for coronary artery disease. Curr Treat Options Cardiovasc Med 2002; 4: 65–74.

    Article  Google Scholar 

  21. Faries PL, Pomposelli Jr FB, Quist WC, LoGerfo FW . Assessing the role of gene therapy in the treatment of vascular disease. Ann Vasc Surg 2000; 14: 181–188.

    Article  CAS  Google Scholar 

  22. Li J et al. PR39, a peptide regulator of angiogenesis. Nat Med 2000; 6: 49–55.

    Article  CAS  Google Scholar 

  23. Byun J et al. Efficient expression of the vascular endothelial growth factor gene in vitro and in vivo, using an adeno-associated virus vector. J Mol Cell Cardiol 2001; 33: 295–305.

    Article  CAS  Google Scholar 

  24. Shimpo M et al. AAV-mediated VEGF gene transfer into skeletal muscle stimulates angiogenesis and improves blood flow in a rat hindlimb ischemia model. Cardiovasc Res 2002; 53: 993–1001.

    Article  CAS  Google Scholar 

  25. Taniyama Y et al. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease. Gene Therapy 2001; 8: 181–189.

    Article  CAS  Google Scholar 

  26. Onimaru M et al. Fibroblast growth factor-2 gene transfer can stimulate hepatocyte growth factor expression irrespective of hypoxia-mediated downregulation in ischemic limbs. Circ Res 2002; 91: 923–930.

    Article  CAS  Google Scholar 

  27. Baumgartner I et al. Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor. Ann Intern Med 2000; 132: 880–884.

    Article  CAS  Google Scholar 

  28. Makinen K 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.

    Article  CAS  Google Scholar 

  29. Lee LY et al. Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor 121. Ann Thorac Surg 2000; 69: 14–23; discussion 23–14.

    Article  CAS  Google Scholar 

  30. Su H, Lu R, Kan YW . Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart. Proc Natl Acad Sci USA 2000; 97: 13801–13806.

    Article  CAS  Google Scholar 

  31. Vincent KA et al. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor. Circulation 2000; 102: 2255–2261.

    Article  CAS  Google Scholar 

  32. Shyu KG et al. Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res 2002; 54: 576–583.

    Article  CAS  Google Scholar 

  33. Laham RJ et al. Longevity of the placebo effect in patients enrolled in angiogenesis and laser myocardial revascularization trials. J Am Coll Cardiol 2002; 39: 11A.

    Article  Google Scholar 

  34. Sarkar N et al. Effects of intramyocardial injection of phVEGF-A165 as sole therapy in patients with refractory coronary artery disease – 12-month follow-up: angiogenic gene therapy. J Intern Med 2001; 250: 373–381.

    Article  CAS  Google Scholar 

  35. Vale PR et al. Effective gene transfer of phVEGF-2 for therapeutic angiogenesis in chronic myocardial ischemia as assessed by NOGATM left ventricular electromechanical mapping. Circulation 2000; 102: II689.

    Article  Google Scholar 

  36. Vale PR et al. Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia. Circulation 2001; 103: 2138–2143.

    Article  CAS  Google Scholar 

  37. Losordo DW et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002; 105: 2012–2018.

    Article  CAS  Google Scholar 

  38. Huwer H et al. Simultaneous surgical revascularization and angiogenic gene therapy in diffuse coronary artery disease. Eur J Cardiothorac Surg 2001; 20: 1128–1134.

    Article  CAS  Google Scholar 

  39. Grines CL et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002; 105: 1291–1297.

    Article  CAS  Google Scholar 

  40. Ruel M et al. Inhibited angiogenic response to surgical FGF-2 protein therapy in a swine model of endothelial dysfunction. Circulation (in press).

  41. Dor Y et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 2002; 21: 1939–1947.

    Article  CAS  Google Scholar 

  42. Ruel M et al. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J Thorac Cardiovasc Surg 2002; 124: 28–34.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported in part by NIH Grants MO1-RR01032 and HL63609 (RJL), and HL46716 and HL69024 (FWS). Dr Khan is supported by an NIH Individual National Research Service Award, HL69651-01.

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Authors and Affiliations

  1. Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    T A Khan & F W Sellke

  2. Division of Cardiology and Angiogenesis Research Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    R J Laham

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  2. F W Sellke
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  3. R J Laham
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Khan, T., Sellke, F. & Laham, R. Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia. Gene Ther 10, 285–291 (2003). https://doi.org/10.1038/sj.gt.3301969

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