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Myocardial gene therapy

Abstract

Gene therapy is proving likely to be a viable alternative to conventional therapies in coronary artery disease and heart failure. Phase 1 clinical trials indicate high levels of safety and clinical benefits with gene therapy using angiogenic growth factors in myocardial ischaemia. Although gene therapy for heart failure is still at the pre-clinical stage, experimental data indicate that therapeutic angiogenesis using short-term gene expression may elicit functional improvement in affected individuals.

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Figure 1: Delivery options for implementing myocardial gene transfer.
Figure 2: Strategies of gene transfer for treatment of heart failure.

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References

  1. Takeshita, S. et al. Therapeutic angiogenesis: a single intra-arterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hindlimb model. J. Clin. Invest. 93, 662–670 (1994).

    Article  CAS  Google Scholar 

  2. Isner, J. M. et al. Arterial gene therapy for therapeutic angiogenesis in patients with peripheral artery disease. Circulation 91, 2687–2692 (1995).

    Article  CAS  Google Scholar 

  3. Isner, J. M. et al. Clinical evidence of angiogenesis following arterial gene transfer of phVEGF165 . Lancet 348, 370–374 (1996).

    Article  CAS  Google Scholar 

  4. Baumgartner, I. et al. Constitutive expression of phVEGF165 following intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischaemia. Circulation 97, 1114–1123 (1998).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Losordo, D. W. et al. Use of the rabbit ear artery to serially assess foreign protein secretion after site specific arterial gene transfer in vivo: evidence that anatomic identification of successful gene transfer may underestimate the potential magnitude of transgene expression. Circulation 89, 785–792 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Grimes, C. Adenovirus FGF angiogenic gene therapy (AGENT) trial. Presented at Late-Breaking Clinical Trials session of 50th annual American College of Cardiology, Orlando, FL, 19 March (2001).

  9. Wolff, J. A. et al. Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468 (1990).

    Article  ADS  CAS  Google Scholar 

  10. Takeshita, S., Isshiki, T. & Sato, T. Increased expression of direct gene transfer into skeletal muscles observed after acute ischemic injury in rats. Lab. Invest. 74, 1061–1065 (1996).

    CAS  PubMed  Google Scholar 

  11. Gal, D. et al. Direct myocardial transfection in two animal models: evaluation of parameters affecting gene expression and percutaneous gene delivery. Lab. Invest. 68, 18–25 (1993).

    CAS  PubMed  Google Scholar 

  12. Rauh, G., Pieczek, A., Irwin, W., Schainfeld, R. & Isner, J. M. In vivo analysis of intramuscular gene transfer in human subjects studied by on-line ultrasound imaging. Hum. Gene Ther. (in the press).

  13. Tio, R. A. et al. Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium. Hum. Gene Ther. 10, 2953–2960 (1999).

    Article  CAS  Google Scholar 

  14. Esakof, D. D. et al. Intraoperative multiplane transesophageal echocardiograpy for guiding direct myocardial gene transfer of vascular endothelial growth factor in patients with refractory angina pectoris. Hum. Gene Ther. 10, 2315–2323 (1999).

    Article  Google Scholar 

  15. Hartikka, J. et al. An improved plasmid DNA expression vector for direct injection into skeletal muscle. Hum. Gene Ther. 7, 1205–1217 (1996).

    Article  CAS  Google Scholar 

  16. Schratzberger, P. et al. Ultrasound enhances therapeutic gene expression in ischemic pig myocardium. J. Am. College Cardiol. 37, 266A (2001).

  17. Taniyama, Y. et al. Local delivery of naked plasmid DNA of P53 gene into rat balloon injured carotid artery using low voltage ultrasound with contrast microbubbles (optison): development of novel non-viral transfection system into blood vessels. Circulation 102, II-164 (2000).

    Article  Google Scholar 

  18. Risau, W. Differentiation of endothelium. FASEB J. 9, 926–933 (1995).

    Article  CAS  Google Scholar 

  19. Allen, K. B. et al. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N. Engl. J. Med. 341, 1029–1036 (1999).

    Article  CAS  Google Scholar 

  20. Symes, J. F. et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease: preliminary clinical results. Ann Thor. Surg. 68, 830–837 (1999).

    Article  CAS  Google Scholar 

  21. Rosengart, T. K. et al. Video assisted epicardial delivery of angiogenic gene therapy to the human myocardium utilizing an adenovirus vector encoding for VEGF121 . Circulation 100, I-770 (1999).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Iwaguro, H. et al. Angiogenesis induced by adenovirus-mediated gene transfer of a hypoxia-inducible factor-1α/VP16 hybrid in rabbit hindlimb ischaemia. Circulation 100, I-47 (1999).

    Google Scholar 

  24. 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 in patients with chronic myocardial ischaemia. Circulation 103, 2138–2143 (2001).

    Article  CAS  Google Scholar 

  25. Shah, A. S. et al. In vivo ventricular gene delivery of a β-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 103, 1311–1316 (2001).

    Article  CAS  Google Scholar 

  26. Seidman, J. G. & Seidman, C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell 104, 557–567 (2001).

    Article  CAS  Google Scholar 

  27. Schmidt, U. et al. Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J. Mol. Cell Cardiol. 30, 1929–1937 (1998).

    Article  CAS  Google Scholar 

  28. Miyamoto, M. I. et al. Adenoviral gene transfer of SERCA2a improves left ventricular function in aortic-banded rats in transition to heart failure. Proc. Natl Acad. Sci. USA 97, 793–798 (2000).

    Article  ADS  CAS  Google Scholar 

  29. Hajjar, R. J., del Monte, F., Matsui, T. & Rosenzweig, A. Prospects for gene therapy for heart failure. Circ. Res. 86, 616–621 (2000).

    Article  CAS  Google Scholar 

  30. He, H. et al. Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J. Clin. Invest. 100, 380–389 (1997).

    Article  CAS  Google Scholar 

  31. Periasamy, M. Adenoviral-mediated SERCA gene transfer into cardiac myocytes. How much is too much? Circulation 88, 373–375 (2001).

    Article  CAS  Google Scholar 

  32. He, H. et al. Effects of mutant and antisense RNA of phospho-lamban on SR Ca2+-ATPase activity and cardiac myocyte contractility. Circulation 100, 974–980 (1999).

    Article  CAS  Google Scholar 

  33. Lefkowitz, R. J., Rockman, H. A. & Koch, W. J. Catecholamines, cardiac “β” adrenergic receptors, and heart failure. Circulation 101, 1634–1637 (2000).

    Article  CAS  Google Scholar 

  34. Maurice, J. P. et al. Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery. J. Clin. Invest. 104, 21–29 (1999).

    Article  CAS  Google Scholar 

  35. Weig, H.-J. et al. Enhanced cardiac contractility after gene transfer of V2 vasopressin receptors in vivo by ultrasound-guided injection of transcoronary delivery. Circulation 101, 1578–1585 (2000).

    Article  CAS  Google Scholar 

  36. White, D. C., Hata, J. A. & Shah, A. S. Preservation of β-adrenergic receptor signaling delays the development of heart failure after myocardial infarction. Proc. Natl Acad. Sci. USA 97, 5428–5433 (2000).

    Article  ADS  CAS  Google Scholar 

  37. Lai, N. C. et al. Intracoronary delivery of adenovirus encoding adenylyl cyclase VI increases left ventricular function and cAMP-generating capacity. Circulation 102, 2396–2401 (2000).

    Article  CAS  Google Scholar 

  38. Haunsetter, A. & Izumo, S. Toward antiapoptosis as a new treatment modality. Circ. Res. 86, 371–376 (2000).

    Article  Google Scholar 

  39. Hirota, H. et al. Loss of gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97, 189–198 (1999).

    Article  CAS  Google Scholar 

  40. Krishenbaum, L. A. & de Moissac, D. The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 96, 1580–1585 (1997).

    Article  Google Scholar 

  41. Matsui, T. et al. Adenoviral gene transfer of activated PI 3-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 275, 661–665 (1999).

    Google Scholar 

  42. Fujio, Y., Nguyen, T., Wencker, D., Kitsis, R. N. & Walshi, K. Akt promotes survival of cardiomyocytes in vitro and protects against ischaemia-reperfusion injury in mouse heart. Circulation 101, 660–667 (2000).

    Article  CAS  Google Scholar 

  43. Mack, C. A. et al. Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart. J. Thor. Cardiovasc. Surg. 115, 168–176 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. O'Donnell, J. M. et al. Tight control of exogenous SERCA expression is required to obtain acceleration of calcium transients with minimal cytotoxic effects in cardiac myocytes. Circ. Res. 88, 415–421 (2001).

    Article  CAS  Google Scholar 

  46. 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).

    Article  CAS  Google Scholar 

  47. Su, H., Lu, R. & Kan, Y. W. Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart. Proc. Natl Acad. Sci. USA 97, 13801–13806 (2000).

    Article  ADS  CAS  Google Scholar 

  48. Blau, H. M. & Banfi, A. The well-tempered vessel. Nature Med. 7, 532–534 (2001).

    Article  CAS  Google Scholar 

  49. Weber, K. T. et al. Fibrillar collagen and remodeling of dilated canine left ventricle. Circulation 82, 1387–1401 (1990).

    Article  CAS  Google Scholar 

  50. Sabbah, H.N., Sharov, V. G., Lesch, M. & Godlstein, S. Progression of heart failure: a role for interstitial fibrosis. Mol. Cell Biochem. 147, 29–34 (1995).

    Article  CAS  Google Scholar 

  51. van den Heuvel, A. F. M. et al. Regional myocardial blood flow reserve impairment and metabolic changes suggesting myocardial ischaemia in patients with idiopathic dilated cardiomyopathy. J. Am. College Cardiol. 35, 19–28 (2000).

    Article  CAS  Google Scholar 

  52. Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF188 . Nature Med. 5, 495–502 (1999).

    Article  CAS  Google Scholar 

  53. Tomanek, R. J. Formation of the coronary vasculature: a brief review. Cardiovasc. Res. 31, E46–E51 (1996).

    Article  Google Scholar 

  54. Gerber, H. P. et al. Knock out of VEGF in ventricular cardiomyocytes leads to increased embryonic lethality and severe cardiac defects in surviving mice. Abstr. Poster Presentation 120, 2000 Keystone Conference on Angiogenesis, 3 March 2000, Salt Lake City, UT (2000).

  55. White, F. C., Carroll, S. M., Magnet, A. & Bloor, C. M. Coronary collateral development in swine after coronary artery occlusion. Circ. Res. 71, 1490–1500 (1992).

    Article  CAS  Google Scholar 

  56. Takeshita, S. et al. Use of synchrotron radiation microangiography to assess development of small collateral arteries in a rat model of hindlimb ischaemia. Circulation 95, 805–808 (1997).

    Article  CAS  Google Scholar 

  57. Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

    Article  CAS  Google Scholar 

  58. Asahara, T. et al. Gene therapy of endothelial progenitor cell for vascular development in severe ischemic disease. Circulation 100, I–481 (1999).

    Google Scholar 

  59. Asahara, T. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ. Res. 85, 221–228 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  61. Kalka, C. et al. Mobilization of endothelial progenitor cells following gene therapy with VEGF165 in patients with inoperable coronary disease. Ann. Thor. Surg. 70, 829–834 (2000).

    Article  CAS  Google Scholar 

  62. Shi, Q. et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 92, 362–367 (1998).

    CAS  PubMed  Google Scholar 

  63. Crosby, J. R. et al. Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation. Circ. Res. 87, 728–730 (2000).

    Article  CAS  Google Scholar 

  64. Kalka, C. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc. Natl Acad. Sci. USA 97, 3422–3427 (2000).

    Article  ADS  CAS  Google Scholar 

  65. Kawamoto, A. et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischaemia. Circulation 103, 634–637 (2001).

    Article  CAS  Google Scholar 

  66. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    Article  CAS  Google Scholar 

  67. Menache, P. Autologous skeletal myoblast transplantation for ischemic cardiomyopathy: first clinical case. Cardiac Vasc. Regen. 1, 155–156 (2000).

    Google Scholar 

  68. Ellis, M. J., Russell, S. D. & Taylor, D. A. Translating cell transfer for cardiovascular disease to the bedside: a preclinical review and discussion of potential early trials. Cardiac Vasc. Regen. 1, 197–204 (2000).

    Google Scholar 

  69. Taylor, D. A. et al. Regenerating functional myocardium: improved performance after skeletal transplantation. Nature Med. 4, 929–933 (1998).

    Article  CAS  Google Scholar 

  70. Cherwek, D., Hopkins, M. B., Hutcheson, K. A., Urbaniak, J. R. & Taylor, D. A. Relieving exercise intolerance secondary to heart failure: myoblast-mediated angiogenesis via VEGF delivery to ischemic skeletal muscle. Circulation 100, I-657 (1999).

    Google Scholar 

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Isner, J. Myocardial gene therapy. Nature 415, 234–239 (2002). https://doi.org/10.1038/415234a

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