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Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer

Gene Therapy volume 16, pages 629–634 (2009)Cite this article

Abstract

Vascular endothelial growth factor (VEGF) has been shown to stimulate angiogenesis and myocardial perfusion. The short-term safety of VEGF gene therapy is excellent. However, there are only limited results regarding the long-term effects. The Kuopio Angiogenesis Trial (KAT) studied the efficiency and short-term safety of the local VEGF-A165 gene transfer in 103 patients with coronary artery disease. Three patient groups received either VEGF as an adenoviral (n=37), or as a plasmid/liposome vector (n=28), or as a placebo (n=38), during coronary angioplasty and stenting (percutaneous coronary intervention, PCI)AQ1. The aim of this study was to examine the long-term effects and safety of VEGF gene therapy. Patients were interviewed by telephone or with a questionnaire on their current status of health, coronary and other cardiovascular events and symptoms, working ability, exercise tolerance, other diseases, such as cancer and diabetes, as well as their personal experience of the treatment. Causes of death were clarified from hospital records. The total follow-up time was 8.1 years (range 6.9–9.7 years). Overall 82% of the patients were reached across the study. Eight (7.5%) of the patients died during the follow-up, but there was no significant difference in mortality between the groups (3/32 vs 2/26 vs 3/31 VEGF-adenovirus vs VEGF-plasmid/liposome vs placebo, respectively; P=0.88). The incidence of major adverse cardiovascular events (MACEs) (10 vs 11 vs 15; P=0.85), cancer (1 vs 4 vs 2; P=0.38) or diabetes (2 vs 2 vs 2; P=0.97) did not differ between the groups. Local intracoronary VEGF gene transfer is safe and does not increase the risk of MACE, arrhythmias, cancer, diabetes or other diseases.

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References

  1. Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K 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.

    Article  CAS  Google Scholar 

  2. Hedman M, Hartikainen J, Syvänne M, Stjernvall J, Hedman A, Kivelä A et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: Phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 2003; 107: 2677–2683.

    Article  CAS  Google Scholar 

  3. Laitinen M, Zachary I, Breier G, Pakkanen T, Häkkinen T, Luoma J et al. VEGF gene transfer reduces intimal thickening via increased production of nitric oxide in carotid arteries. Hum Gene Ther 1997; 8: 1737–1744.

    Article  CAS  Google Scholar 

  4. Mäkinen K, Manninen H, Hedman M, Matsi P, Mussalo H, Alhava E 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  Google Scholar 

  5. Ylä-Herttuala S, Martin JF . Cardiovascular gene therapy. Lancet 2000; 335: 213–222.

    Article  Google Scholar 

  6. Ylä-Herttuala S, Alitalo K . Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 2003; 9: 694–701.

    Article  Google Scholar 

  7. Ylä-Herttuala S, Rissanen T, Vajanto I, Hartikainen J . Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 2007; 49: 1015–1026.

    Article  Google Scholar 

  8. Gaffney MM, Hynes SO, Barry F, O'Brien T . Cardiovascular gene therapy: current status and therapeutic potential. Br J Pharmacol 2007; 152: 175–188.

    Article  CAS  Google Scholar 

  9. Laitinen M, Mäkinen K, Manninen H, Matsi P, Kossila M, Agrawal R et al. Adenovirus-mediated gene transfer to lower limb artery of patients with chronic critical leg ischaemia. Hum Gene Ther 1998; 9: 1481–1486.

    Article  CAS  Google Scholar 

  10. Kusumanto YH, van Weel V, Mulder NH, Smit AJ, van Dungen JJ, Hooymans JM 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.

    Article  CAS  Google Scholar 

  11. Laitinen M, Pakkanen T, Donetti E, Baetta R, Luoma J, Viita H 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 1998; 8: 1645–1650.

    Article  Google Scholar 

  12. Puumalainen AM, Vapalahti M, Agrawal RS, Kossila RS, Laukkanen J, Lehtolainen P et al. Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 1998; 9: 1769–1774.

    Article  CAS  Google Scholar 

  13. Wirth T, Hedman M, Mäkinen K, Manninen H, Immonen A, Vapalahti M et al. Safety profile of plasmid/liposomes and virus vectors in clinical gene therapy. Curr Drug Saf 2006; 1: 253–257.

    Article  CAS  Google Scholar 

  14. Alton EW, Stern M, Farley R, Jaffe A, Chadwick SL, Phillips J et al. Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial. Lancet 1999; 353: 947–954.

    Article  CAS  Google Scholar 

  15. Shayakhmetov DM, Gaggar A, Ni S, Li Z-Y, Lieber A . Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. J Virol 2005; 79: 7478–7491.

    Article  CAS  Google Scholar 

  16. Grines CL, Watkins MW, Mahmarian JJ, Iskandrian AE, Rade JJ, Marrot P et al. Angiogene GENe Therapy (AGENT-2) Study Group. A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. J Am Coll Cardiol 2003; 42: 1339–1347.

    Article  CAS  Google Scholar 

  17. Henry TD, Grines CL, Watkins MW, Dib N, Barbeau G, Moreadith R et al. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol 2007; 50: 1038–1046.

    Article  CAS  Google Scholar 

  18. Kastrup J, Jørgensen E, Rück A, Tägil K, Glogar D, Ruzyllo W, et al., The Euroinject One Group. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris: A randomized double-blind placebo-controlled study: The Euroinject One Trial. J Am Coll Cardiol 2005; 45: 982–988.

    Article  CAS  Google Scholar 

  19. Stewart DJ, Hilton JD, Arnold JM, Gregoire J, Rivard A, Archer SL et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) versus maximum medical treatment. Gene Therapy 2006; 13: 1503–1511.

    Article  CAS  Google Scholar 

  20. Leppänen P, Koota S, Kholová I, Koponen J, Fieber C, Eriksson U et al. Gene transfers of vascular endothelial growth factor-A, vascular endothelial growth factor-B, vascular endothelial growth factor-C, and vascular endothelial growth factor-D have no effects on atherosclerosis in hypercholesterolemic low-density lipoprotein-receptor/apolipoprotein B48-deficient mice. Circulation 2005; 112: 1347–1352.

    Article  Google Scholar 

  21. Rutanen J, Rissanen TT, Markkanen JE, Gruchala M, Kivelä A, Hedman A et al. Adenoviral catheter-mediated intramyocardial VEGF-DΔNΔC gene transfer induces transmural angiogenesis in porcine heart. Circulation 2004; 109: 1029–1035.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by grants from the Kuopio University Hospital and the Helsinki University Central Hospital (EVO Grants). The Finnish Academy, Finnish Foundation for Cardiovascular Research, Clinigene EU network of excellence (LSHB-CT-2006-018933) and Ark Therapeutics Ltd. have also supported this study.

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Authors and Affiliations

  1. Department of Medicine, Kuopio University Hospital, Kuopio, Finland

    M Hedman, K Muona, A Hedman, A Kivelä, J Eränen, A Rantala, J Hartikainen & S Ylä-Herttuala

  2. Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland

    M Syvänne, J Stjernvall & M S Nieminen

  3. Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland

    S Ylä-Herttuala

  4. Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland

    S Ylä-Herttuala

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  1. M Hedman
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  2. K Muona
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  4. A Kivelä
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  9. M S Nieminen
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Correspondence to S Ylä-Herttuala.

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Hedman, M., Muona, K., Hedman, A. et al. Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer. Gene Ther 16, 629–634 (2009). https://doi.org/10.1038/gt.2009.4

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