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Gene transfer as a tool to induce therapeutic vascular growth

Nature Medicine volume 9, pages 694–701 (2003)Cite this article

Abstract

Therapeutic induction of vascular growth may provide a treatment option for those patients with myocardial or peripheral ischemia who are not suited to conventional revascularization therapies. Some lymphatic vascular disorders may also be amenable to this therapy. However, clear evidence of efficacy must be obtained from phase 2 and 3 clinical trials before these new treatments can be entered into clinical practice. Apart from the clinical applications, gene transfer aimed at stimulating or blocking vascular growth with various growth factors, cytokines, transcription factors and receptors or their antagonists is useful for analyzing the effects of those molecules on the vasculature, especially when gene targeting results in lethality or when large animal models are required.

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Figure 1: Clinically feasible gene delivery routes to induce therapeutic vascular growth.

Debbie Maizels

Figure 2: Therapeutic vascular growth achieved by gene transfer in vivo.
Figure 3: Low gene transfer efficiency is a major problem in human gene therapy.

Debbie Maizels

Figure 4: Increased vascularity after adenovirus-mediated VEGF gene therapy in human limb.

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References

  1. Ylä-Herttuala, S. & Martin, J.F. Cardiovascular gene therapy. Lancet 355, 213–222 (2000).

    PubMed  Google Scholar 

  2. Kootstra, N.A. & Verma, I.M. Gene therapy with viral vectors. Annu. Rev. Pharmacol. Toxicol. 43, 413–439 (2002).

    PubMed  Google Scholar 

  3. Laitinen, M. et al. Gene transfer into the carotid artery using an adventitial collar. Comparison of the effectiveness of plasmid-liposome complexes, retroviruses, pseudotyped retroviruses and adenoviruses. Hum. Gene Ther. 8, 1645–1650 (1997).

    CAS  PubMed  Google Scholar 

  4. Tripathy, S.K. et al. Long-term expression of erythropoietin in the systemic circulation of mice after intramuscular injection of a plasmid DNA vector. Proc. Natl. Acad. Sci. USA 93, 10876–10880 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bergelson, J.M. et al. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323 (1997).

    CAS  PubMed  Google Scholar 

  6. Wickham, T.J. et al. Integrins αvβ3 and αvβ5 promote adenovirus internalisation but not virus attachment. Cell 73, 309–319 (1993).

    CAS  PubMed  Google Scholar 

  7. Yang, Y. et al. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc. Natl. Acad. Sci. USA 91, 4407–4411 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lehrman, S. Virus treatment questioned after gene therapy death. Nature 401, 517–518 (1999).

    CAS  PubMed  Google Scholar 

  9. Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).

    CAS  PubMed  Google Scholar 

  10. Trono, D. Lentiviral vectors: turning a deadly foe into a therapeutic agent. Gene Ther. 7, 20–23 (2000).

    CAS  PubMed  Google Scholar 

  11. Svensson, E.C. et al. Efficient and stable transduction of cardiomyocytes after intramyocardial injection or intracoronary perfusion with recombinant adeno-associated virus vectors. Circulation 99, 201–205 (1999).

    CAS  PubMed  Google Scholar 

  12. Monahan, P.E. & Samulski, R.J. AAV vectors: is clinical success on the horizon? Gene Ther. 7, 24–30 (2000).

    CAS  PubMed  Google Scholar 

  13. Mesri, E.A., Federoff, H.J. & Brownlee, M. Expression of vascular endothelial growth factor from a defective herpes simplex virus type 1 amplicon vector induces angiogenesis in mice. Circ Res. 76, 161–167 (1995).

    CAS  PubMed  Google Scholar 

  14. Fukumura, M. et al. Gene transfer to skeletal muscle and motor neurons by intramuscular injection of a novel minus strand RNA vector (Sendai virus vector). J. Gen. Med. 2 (suppl.), 24 (2000).

    Google Scholar 

  15. Airenne, K.J. et al. Baculovirus-mediated periadventitial gene transfer to rabbit carotid artery. Gene Ther. 7, 1499–1504 (2000).

    CAS  PubMed  Google Scholar 

  16. Springer, M.L., Chen, A.S., Kraft, P.E., Bednarski, M. & Blau, H.M. VEGF gene delivery to muscle: potential role for vasculogenesis in adults. Mol. Cell. 2, 549–558 (1998).

    CAS  PubMed  Google Scholar 

  17. Clackson, T. Regulated gene expression systems. Gene Ther. 7, 120–125 (2000).

    CAS  PubMed  Google Scholar 

  18. Greco, O. et al. Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. Gene Ther. 9, 1403–1411 (2002).

    CAS  PubMed  Google Scholar 

  19. Koponen, J.K. et al. Doxycycline-regulated lentiviral vector system with a novel reverse transactivator rtTA2S-M2 shows a tight control of gene expression in vitro and in vivo. Gene Ther. 10, 459–466 (2003).

    CAS  PubMed  Google Scholar 

  20. McManus, M.T. & Sharp, P.A. Gene silencing in mammals by small interfering RNAs. Nat. Rev. Genet. 3, 737–747 (2002).

    CAS  PubMed  Google Scholar 

  21. Marshall, E. Second child in French trial is found to have leukemia. Science 299, 320 (2003).

    CAS  PubMed  Google Scholar 

  22. Laitinen, M. et al. Adenovirus-mediated gene transfer to lower limb artery of patients with chronic critical leg ischaemia. Hum. Gene Ther. 9, 1481–1486 (1998).

    CAS  PubMed  Google Scholar 

  23. Arras, M. et al. The delivery of angiogenic factors to the heart by microsphere therapy. Nat. Biotechnol. 15, 159–162 (1998).

    Google Scholar 

  24. Villanueva, F.S. et al. Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation 98, 1–5 (1998).

    CAS  PubMed  Google Scholar 

  25. Ruoslahti, E. Specialization of tumour vasculature. Nat. Rev. Cancer 21, 83–90 (2002).

    Google Scholar 

  26. Alitalo, K. & Ferrara, N. Clinical applications of angiogenic growth factors and their inhibitors. Nat. Med. 5, 1359–1364 (1999).

    PubMed  Google Scholar 

  27. Kärkkäinen, M.J. et al. A model for gene therapy of human hereditary lymphedema. Proc. Natl. Acad. Sci. USA 98, 12677–12682 (2001).

    PubMed  PubMed Central  Google Scholar 

  28. Szuba, A. et al. Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB J. 16, 1985–1987 (2002).

    CAS  PubMed  Google Scholar 

  29. Saaristo, A., Karkkainen, M.J. & Alitalo, K. Insights into the molecular pathogenesis and targeted treatment of lymphedema. Ann. NY Acad. Sci. 979, 94–110 (2002).

    CAS  PubMed  Google Scholar 

  30. Leung, D.W., Cachianes, G., Kuang, W.J., Goeddel, D.V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

    CAS  PubMed  Google Scholar 

  31. Dvorak, H.F., Brown, L.F., Detmar, M. & Dvorak, A.M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146, 1029–1039 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Olofsson, B. et al. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc. Natl. Acad. Sci. USA. 93, 2576–2581 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Joukov, V. et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases EMBO J. 15, 290–298 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Achen, M.G. et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc. Natl. Acad. Sci. USA. 95, 548–553 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ogawa, S. et al. A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J. Biol. Chem. 273, 31273–31282 (1998).

    CAS  PubMed  Google Scholar 

  36. Park, J.E., Chen, H.H., Winer, J., Houck, K.A. & Ferrara, N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J. Biol. Chem. 269, 25646–25654 (1994).

    CAS  PubMed  Google Scholar 

  37. Neufeld, G., Cohen, T., Gengrinovitch, S. & Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13, 9–22 (1999).

    CAS  PubMed  Google Scholar 

  38. Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 8, 831–840 (2002).

    CAS  PubMed  Google Scholar 

  39. Hattori, K. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment. Nat. Med. 8, 841–849 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Arras, M. et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J. Clin. Invest. 101, 40–50 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Rissanen, T.T. et al. Effects of VEGF-D gene transfer on vascular permeability and angiogenesis in rabbit skeletal muscle – comparison with other VEGFs. Circ. Res. (in the press).

  42. Dor, Y. et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 21, 1939–1947 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Rissanen, T.T., Vajanto, I. & Ylä-Herttuala, S. Gene therapy for therapeutic angiogenesis in critically ischaemic lower limb – on the way to the clinic. Eur. J. Clin. Invest. 31, 651–666 (2001).

    CAS  PubMed  Google Scholar 

  44. Saaristo, A. et al. Lymphangiogenic gene therapy with minimal blood vascular side effects. J. Exp. Med. 196, 719–730 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Yoon, Y. et al. VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. J. Clin. Invest. 111, 717–725 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Isner, J.M., Vale, P.R., Symes, J.F. & Losordo, D.W. Assessment of risks associated with cardiovascular gene therapy in human subjects. Circ. Res. 89, 389–400 (2001).

    CAS  PubMed  Google Scholar 

  47. Davis, S. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996).

    CAS  PubMed  Google Scholar 

  48. Maisonpierre, P.C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).

    CAS  PubMed  Google Scholar 

  49. Shyu, K.G., Manor, O., Magner, M., Yancopoulos, G.D. & Isner, J.M. Direct intramuscular injection of plasmid DNA encoding angiopoietin-1 but not angiopoietin-2 augments revascularization in the rabbit ischemic hindlimb. Circulation 98, 2081–2087 (1998).

    CAS  PubMed  Google Scholar 

  50. Chae, J.K. et al. Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscler. Thromb. Vasc. Biol. 20, 2573–2578 (2000).

    CAS  PubMed  Google Scholar 

  51. Arsic, N. et al. Induction of functional neovascularization by combined VEGF and angiopoietin-1 gene transfer using AAV vectors. Mol. Ther. 7, 450–459 (2003).

    CAS  PubMed  Google Scholar 

  52. Javerzat, S., Auguste, P. & Bikfalvi, A. The role of fibroblast growth factors in vascular development. Trends Mol. Med. 10, 483–489 (2002).

    Google Scholar 

  53. Galzie, Z., Kinsella, A.R. & Smith, J.A. Fibroblast growth factors and their receptors. Biochem. Cell Biol. 75, 669–685 (1997).

    CAS  PubMed  Google Scholar 

  54. Miller, D.L. et al. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2-null mice. Mol. Cell Biol. 20, 2260–2268 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Xu, X., Weinstein, M., Li, C. & Deng, C. Fibroblast growth factor receptors (FGFRs) and their roles in limb development. Cell Tissue Res. 296, 33–43 (1999).

    CAS  PubMed  Google Scholar 

  56. Rissanen, T.T. et al. Fibroblast growth factor-4 induces vascular permeability, angiogenesis and arteriogenesis in a rabbit hindlimb ischemia model. FASEB J. 17, 100–102 (2003).

    CAS  PubMed  Google Scholar 

  57. Kubo, H. et al. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc. Natl. Acad. Sci. USA 99, 8868–8873 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Giordano, F.J. et al. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischaemic region of the heart. Nat. Med. 2, 534–539 (1996).

    CAS  PubMed  Google Scholar 

  59. Simons, M. et al. Clinical trials in coronary angiogenesis: issues, problems, consensus. An expert panel summary. Circulation 102, e73–e86 (2000).

    CAS  PubMed  Google Scholar 

  60. Morishita, R. et al. Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 33, 1379–1384 (1999).

    CAS  PubMed  Google Scholar 

  61. Ito, W.D. et al. Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion. Circ. Res. 80, 829–837 (1997).

    CAS  PubMed  Google Scholar 

  62. Takahashi, T. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med. 5, 434–438 (1999).

    CAS  PubMed  Google Scholar 

  63. Cao, R. et al. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat. Med. 9, 604–613 (2003).

    CAS  PubMed  Google Scholar 

  64. Rissanen, T.T. et al. Expression of VEGF and VEGFR-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration. Am. J. Pathol. 160, 1–11 (2002).

    Google Scholar 

  65. Barton-Davis, E.R., Shoturma, D.I., Musaro, A. Rosenthal, N. & Sweeney, H.L. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc. Natl. Acad. Sci. USA 95, 15603–15607 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Penta, K. et al. Del1 induces integrin signaling and angiogenesis by ligation of αvβ3 . J. Biol. Chem. 274, 11101–11109 (1999).

    CAS  PubMed  Google Scholar 

  67. Fataccioli, V. et al. Stimulation of angiogenesis by Cyr61 gene: A new therapeutic candidate. Hum. Gene Ther. 13, 1461–1470 (2002).

    CAS  PubMed  Google Scholar 

  68. Dufourcq, P. et al. FrzA, a secreted frizzled related protein, induced angiogenic response. Circulation 106, 3097–3107 (2002).

    PubMed  Google Scholar 

  69. Emanueli, C. et al. Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs. Circulation 106, 2257–2262 (2002).

    CAS  PubMed  Google Scholar 

  70. Emanueli, C. et al. Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler. Thromb. Vasc. Biol. 20, 2379–2385 (2000).

    CAS  PubMed  Google Scholar 

  71. Smith, R.S. Jr., Lin, K-F., Agata, J., Chao, L. & Chao, J. Human endothelial nitric oxide synthase gene delivery promotes angiogenesis in a rat model of hindlimb ischemia. Arterioscler. Thromb. Vasc. Biol. 22, 1279–1285 (2002).

    CAS  PubMed  Google Scholar 

  72. Vincent, K.A. et al. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1α/VP16 hybrid transcription factor. Circulation 102, 2255–2261 (2000).

    CAS  PubMed  Google Scholar 

  73. Bryant, M. et al. Tissue repair with a therapeutic transcription factor. Hum. Gene Ther. 11, 2143–2158 (2000).

    CAS  PubMed  Google Scholar 

  74. Petrova, T.V. et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J. 21, 4593–4599 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Rebar, E.J. et al. Induction of angiogenesis in a mouse model using engineered transcription factors. Nat. Med. 8, 1427–1433 (2002).

    CAS  PubMed  Google Scholar 

  76. Romano Di Peppe, S. et al. Adenovirus-mediated VEGF165 gene transfer enhances wound healing by promoting angiogenesis in CD1 diabetic mice. Gene Ther. 9, 1271–1277 (2002).

    CAS  PubMed  Google Scholar 

  77. Deodato, B. et al. Recombinant AAV vector encoding human VEGF165 enhances wound healing. Gene Ther. 12, 777–785 (2002).

    Google Scholar 

  78. Rockson, S.G. Lymphedema. Am. J. Med. 110, 288–295 (2001).

    CAS  PubMed  Google Scholar 

  79. Karkkainen, M.J. et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat. Genet. 25, 153–159 (2000).

    CAS  PubMed  Google Scholar 

  80. Wright, M.J., Wightman, L.M., Latchman, D.S. & Marber, M.S. In vivo myocardial gene transfer: optimization and evaluation of intracoronary gene delivery in vivo. Gene Ther. 8, 1833–1839 (2001).

    CAS  PubMed  Google Scholar 

  81. Vitadello, M., Schiaffino, M.V., Picard, A., Scarpa, M. & Schiaffino, S. Gene transfer in regenerating muscle. Hum. Gene Ther. 5, 11–18 (1994).

    CAS  PubMed  Google Scholar 

  82. Schratzberger, P. et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J. Clin. Invest. 107, 1083–1092 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Isner, J.M. et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 348, 370–374 (1996).

    CAS  PubMed  Google Scholar 

  84. Baumgartner, I. et al. Constitutive expression of VEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 97, 1114–1123 (1998).

    CAS  PubMed  Google Scholar 

  85. Isner, J.M. et al. Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J. Vasc. Surg. 28, 964–973 (1998).

    CAS  PubMed  Google Scholar 

  86. Losordo, D.W. et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischaemia. Circulation 98, 2800–2804 (1998).

    CAS  PubMed  Google Scholar 

  87. Rosengart, T.K. et al. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 100, 468–474 (1999).

    CAS  PubMed  Google Scholar 

  88. Symes, J.F. et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann. Thorac. Surg. 68, 830–837 (1999).

    CAS  PubMed  Google Scholar 

  89. Vale, P.R. et al. Left ventricular electromechanical mapping to assess efficacy of phVEGF165 gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 102, 965–974 (2000).

    CAS  PubMed  Google Scholar 

  90. Laitinen, M. et al. Catheter-mediated vascular endothelial growth factor gene transfer to human coronary arteries after angioplasty. Hum. Gene Ther. 11, 263–270 (2000).

    CAS  PubMed  Google Scholar 

  91. Vale, P.R. et al. Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping of patients with chronic myocardial ischemia. Circulation 103, 2138–2143 (2001).

    CAS  PubMed  Google Scholar 

  92. Rajagopalan, S., Shah, M., Luciano, A., Crystal, R. & Nabel, E.G. Adenovirus-mediated gene transfer of VEGF121 improves lower-extremity endothelial function and flow reserve. Circulation 104, 753–755 (2001).

    CAS  PubMed  Google Scholar 

  93. 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. 250, 373–381 (2001).

    CAS  PubMed  Google Scholar 

  94. Comerota, A.J. 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. 35, 930–936 (2002).

    PubMed  Google Scholar 

  95. Losordo, D.W. 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 105, 2012–2018 (2002).

    CAS  PubMed  Google Scholar 

  96. Shyu, K.G., Chang, H., Wang, B.W. & Kuan, P. Intramuscular vascular endothelial growth factor gene therapy in patients with chronic critical leg ischemia. Am. J. Med. 114, 85–92 (2003).

    CAS  PubMed  Google Scholar 

  97. Henry, T.D. et al. The VIVA trial. Vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107, 1359–1365 (2003).

    CAS  PubMed  Google Scholar 

  98. Simons, M. et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2. Circulation 105, 788–793 (2002).

    CAS  PubMed  Google Scholar 

  99. Lederman, R.J. et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 359, 2053–2058 (2002).

    CAS  PubMed  Google Scholar 

  100. Seiler, C. et al. Promotion of collateral growth by granulocyte-macrophage colony-stimulating factor in patients with coronary artery disease. Circulation 104, 2012–2017 (2001).

    CAS  PubMed  Google Scholar 

  101. Grines, C.L. et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105, 1291–1297 (2002).

    CAS  PubMed  Google Scholar 

  102. Mäkinen, K. et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery. Mol. Ther. 6, 127–133 (2002).

    PubMed  Google Scholar 

  103. Hedman, M. et al. Safety and feasibility of catheter-based local intracoronary VEGF gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia. Circulation (in the press).

  104. Stewart, D.J. et al. A phase 2, randomised, multicenter, 26-week study to assess the efficacy and safety of BIOBYPASS (AdGVVEGF121) delivered through minimally invasive surgery versus maximum medical treatment in patients with severe angina, advanced coronary artery disease, and no options for revascularizations. Circulation 106, 23–26 (2002).

    Google Scholar 

  105. Rajagopalan, S. et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease (RAVE). Late breaking clinical trials session. American College of Cardiology 2003, Chicago. J. Am. Coll. Cardiol. 41, 1604 (2003).

    Google Scholar 

  106. Kastrup, J. et al. Euroinject One trial. Late breaking clinical trials session. American College of Cardiology 2003, Chicago. J. Am. Coll. Cardiol. 41, 1603 (2003).

    Google Scholar 

  107. Pislaru, S., Janssens, S.P., Gersh, B.J. & Simari, R.D. Defining gene transfer before gene therapy. Circulation 106, 631–636 (2002).

    CAS  PubMed  Google Scholar 

  108. Hiltunen, M.O. et al. Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta. Circulation 102, 2262–2268 (2000).

    CAS  PubMed  Google Scholar 

  109. Hiltunen, M.O. et al. Biodistribution of adenoviral vector to nontarget tissues after in in vivo gene transfer to arterial wall using intravascular and periadventitial gene delivery methods. FASEB J. 14, 2230–2236 (2000).

    CAS  PubMed  Google Scholar 

  110. Pakkanen, T. et al. Periadventitial lacZ gene transfer to pig carotid arteries using a plasmid-liposome complexes. J. Gene Med. 2, 52–60 (2000).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Our studies were supported by the Finnish Academy of Sciences, the Finnish Technology Development Center, the European Union, the Novo Nordisk Foundation, the Sigrid Jusélius Foundation and the Ludwig Institute for Cancer Research. We thank M. Kärkkäinen, A. Saaristo, T. Rissanen, J. Rutanen and J. Markkanen for discussion and M. Poikolainen for help in preparing the manuscript.

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  1. A.I. Virtanen Institute and Department of Medicine, University of Kuopio and Gene Therapy Unit, Kuopio University Hospital, P.O. Box 1627, Kuopio, FIN-70211, Finland

    Seppo Ylä-Herttuala

  2. Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, The Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, P.O. Box 63, Helsinki, FIN-00014, Finland

    Kari Alitalo

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Ylä-Herttuala, S., Alitalo, K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 9, 694–701 (2003). https://doi.org/10.1038/nm0603-694

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