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Delivery of Gene and Cellular Therapies for Heart Disease

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Abstract

Although there has been considerable interest in the utilization of gene and cellular therapy for heart disease in recent years, there remain critical questions prior to widespread promotion of therapy, and key among these issues is the delivery method used for both gene therapy and cellular therapy. Much of the failure of gene and cellular therapy can be explained by the biological therapy itself; however, certainly there is a critical role played by the delivery technique, in particular, those that have been adapted from routine clinical use such as intravenous and intracoronary injection. Development of novel techniques to deliver gene and cellular therapy has ensued with some preclinical and even clinical success, though questions regarding safety, invasiveness, and repeatability remain. Here, we review techniques for gene and cellular therapy delivery, both existing and adapted techniques, and novel techniques that have emerged recently at promoting improved efficacy of therapy without the cost of systemic distribution. We also highlight key issues that need to be addressed to improve the chances of success of delivery techniques to enhance therapeutic benefit.

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References

  1. Kaye, D. M., et al. (2007). Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals. Journal of the American College of Cardiology, 50(3), 253–260.

    Article  PubMed  CAS  Google Scholar 

  2. Byrne, M. J., et al. (2008). Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals. Gene Therapy, 15(23), 1550–1557.

    Article  PubMed  CAS  Google Scholar 

  3. von Ludinghausen, M. (2003). The venous drainage of the human myocardium. Advances in Anatomy, Embryology, And Cell Biology, 168: I-VIII, 1-104.

  4. Maselli, D., et al. (2006). Percutaneous mitral annuloplasty: an anatomic study of human coronary sinus and its relation with mitral valve annulus and coronary arteries. Circulation, 114(5), 377–380.

    Article  PubMed  Google Scholar 

  5. Gensini, G. G., et al. (1965). Anatomy of the coronary circulation in living man: coronary venography. Circulation, 31(5), 778–784.

    PubMed  CAS  Google Scholar 

  6. Gilard, M., et al. (1998). Angiographic anatomy of the coronary sinus and its tributaries. Pacing Clin Electrophysiol, 21(11 Pt 2), 2280–2284.

    Article  PubMed  CAS  Google Scholar 

  7. Van de Veire, N. R., et al. (2006). Non-invasive visualization of the cardiac venous system in coronary artery disease patients using 64-slice computed tomography. Journal of the American College of Cardiology, 48(9), 1832–1838.

    Article  PubMed  Google Scholar 

  8. Jongbloed, M. R., et al. (2005). Noninvasive visualization of the cardiac venous system using multislice computed tomography. Journal of the American College of Cardiology, 45(5), 749–753.

    Article  PubMed  Google Scholar 

  9. Potkin, B. N., & Roberts, W. C. (1987). Size of coronary sinus at necropsy in subjects without cardiac disease and in patients with various cardiac conditions. American Journal of Cardiology, 60(16), 1418–1421.

    Article  PubMed  CAS  Google Scholar 

  10. Meisel, E., et al. (2001). Investigation of coronary venous anatomy by retrograde venography in patients with malignant ventricular tachycardia. Circulation, 104(4), 442–447.

    Article  PubMed  CAS  Google Scholar 

  11. Angelini, P., et al. (1999). Normal and anomolous coronary arteries in humans. In P. Angelini (Ed.), Coronary artery anomolies. Baltimore: Liipincott Williams and Wilkins.

    Google Scholar 

  12. Williams, P.L., et al. (eds.) (1989). Gray's anatomy, 37 ed. Churchill Livingstone: London. 1598.

  13. Altman, P. A., Sievers, R., & Lee, R. (2003). Exploring heart lymphatics in local drug delivery. Lymphat Res Biol, 1(1), 47–53. discussion 54.

    Article  PubMed  Google Scholar 

  14. Bradham, R. R., et al. (1970). The cardiac lymphatics. Annals of Surgery, 171(6), 899–902.

    Article  PubMed  CAS  Google Scholar 

  15. Moir, T. W., Eckstein, R. W., & Driscol, T. E. (1963). Thebesian drainage of the septal artery. Circulation Research, 12(2), 212–219.

    Google Scholar 

  16. Cui, Y., Urschel, J. D., & Petrelli, N. J. (2001). The effect of cardiopulmonary lymphatic obstruction on heart and lung function. Thoracic and Cardiovascular Surgeon, 49(1), 35–40.

    Article  PubMed  CAS  Google Scholar 

  17. Blaese, R. M., et al. (1995). T lymphocyte-directed gene therapy for ADA-SCID: Initial trial results after 4 years. Science, 270(5235), 475–480.

    Article  PubMed  CAS  Google Scholar 

  18. Elmadbouh, I., et al. (2007). Ex vivo delivered stromal cell-derived factor-1(alpha) promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium. Journal of Molecular and Cellular Cardiology, 42(4), 792–803.

    Article  PubMed  CAS  Google Scholar 

  19. Kypson, A. P., et al. (1998). Ex vivo adenovirus-mediated gene transfer to the adult rat heart. Journal of Thoracic and Cardiovascular Surgery, 115(3), 623–630.

    Article  PubMed  CAS  Google Scholar 

  20. Yap, J., et al. (2001). Conditions of vector delivery improve efficiency of adenoviral-mediated gene transfer to the transplanted heart. European Journal of Cardio-Thoracic Surgery, 19(5), 702–707.

    Article  PubMed  CAS  Google Scholar 

  21. Stadlbauer, T. H. W., et al. (2008). AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts. Cardiovascular Research, 79(4), 698–705.

    Article  PubMed  CAS  Google Scholar 

  22. Schirmer, J. M., et al. (2007). Recombinant adeno-associated virus vector for gene transfer to the transplanted rat heart. Transplant International, 20(6), 550–557.

    Article  PubMed  CAS  Google Scholar 

  23. Lazarous, D. F., et al. (1997). Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution. Cardiovascular Research, 36(1), 78–85.

    Article  PubMed  CAS  Google Scholar 

  24. Barbash, I. M., et al. (2003). Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation, 108(7), 863–868.

    Article  PubMed  Google Scholar 

  25. Hofmann, M., et al. (2005). Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation, 111(17), 2198–2202.

    Article  PubMed  Google Scholar 

  26. Franz, W. M., et al. (1997). Analysis of tissue-specific gene delivery by recombinant adenoviruses containing cardiac-specific promoters. Cardiovascular Research, 35(3), 560–566.

    Article  PubMed  CAS  Google Scholar 

  27. Aikawa, R., Huggins, G. S., & Snyder, R. O. (2002). Cardiomyocyte-specific gene expression following recombinant adeno-associated viral vector transduction. Journal of Biological Chemistry, 277(21), 18979–18985.

    Article  PubMed  CAS  Google Scholar 

  28. Boecker, W., et al. (2004). Cardiac-specific gene expression facilitated by an enhanced myosin light chain promoter. Mol Imaging, 3(2), 69–75.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  30. Lazarous, D. F., et al. (1999). Adenoviral-mediated gene transfer induces sustained pericardial VEGF expression in dogs: effect on myocardial angiogenesis. Cardiovascular Research, 44(2), 294–302.

    Article  PubMed  CAS  Google Scholar 

  31. Hou, D., et al. (2005). Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation, 112(9 Suppl), I150–I156.

    PubMed  Google Scholar 

  32. Nabel, E. G. (2004). Gene transfer approaches for cardiovascular disease. In K. R. Chien (Ed.), Molecular basis of cardiovascular disease: a companion to Braunwald's heart disease (pp. 195–216). Philadelphia: Elsevier.

    Google Scholar 

  33. Parsa, C. J., et al. (2005). Catheter-mediated subselective intracoronary gene delivery to the rabbit heart: introduction of a novel method. Journal of Gene Medicine, 7(5), 595–603.

    Article  PubMed  Google Scholar 

  34. Wright, M. J., et al. (2001). In vivo myocardial gene transfer: optimization and evaluation of intracoronary gene delivery in vivo. Gene Therapy, 8(24), 1833–1839.

    Article  PubMed  CAS  Google Scholar 

  35. Emani, S. M., et al. (2003). Catheter-based intracoronary myocardial adenoviral gene delivery: importance of intraluminal seal and infusion flow rate. Molecular Therapy, 8(2), 306–313.

    Article  PubMed  CAS  Google Scholar 

  36. Wilensky, R. L., et al. (1999). Increased intramural retention after local delivery of molecules with increased binding properties: implications for regional delivery of pharmacologic agents. J Cardiovascular Pharmacological Therapeutics, 4(2), 103–112.

    Article  CAS  Google Scholar 

  37. Sasano, T., et al. (2007). Targeted high-efficiency, homogeneous myocardial gene transfer. Journal of Molecular and Cellular Cardiology, 42(5), 954–961.

    Article  PubMed  CAS  Google Scholar 

  38. Raake, P. W., et al. (2008). Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors. Gene Therapy, 15(1), 12–17.

    Article  PubMed  CAS  Google Scholar 

  39. Donahue, J. K., et al. (1997). Ultrarapid, highly efficient viral gene transfer to the heart. Proceedings of the National Academy of Sciences of the United States of America, 94(9), 4664–4668.

    Article  PubMed  CAS  Google Scholar 

  40. Donahue, J. K., et al. (1998). Acceleration of widespread adenoviral gene transfer to intact rabbit hearts by coronary perfusion with low calcium and serotonin. Gene Therapy, 5(5), 630–634.

    Article  PubMed  CAS  Google Scholar 

  41. Assmus, B., et al. (2002). Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation, 106(24), 3009–3017.

    Article  PubMed  Google Scholar 

  42. Schachinger, V., et al. (2004). Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. Journal of the American College of Cardiology, 44(8), 1690–1699.

    Article  PubMed  Google Scholar 

  43. Schachinger, V., et al. (2006). Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. European Heart Journal, 27(23), 2775–2783.

    Article  PubMed  Google Scholar 

  44. Assmus, B., et al. (2006). Transcoronary transplantation of progenitor cells after myocardial infarction. New England Journal of Medicine, 355(12), 1222–1232.

    Article  PubMed  CAS  Google Scholar 

  45. Meluzin, J., et al. (2009). Intracoronary delivery of bone marrow cells to the acutely infarcted myocardium. Optimization of the delivery technique. Cardiology, 112(2), 98–106.

    Article  PubMed  Google Scholar 

  46. Tossios, P., et al. (2008). Role of balloon occlusion for mononuclear bone marrow cell deposition after intracoronary injection in pigs with reperfused myocardial infarction. European Heart Journal, 29(15), 1911–1921.

    Article  PubMed  CAS  Google Scholar 

  47. Mansour, S., et al. (2006). Intracoronary delivery of hematopoietic bone marrow stem cells and luminal loss of the infarct-related artery in patients with recent myocardial infarction. Journal of the American College of Cardiology, 47(8), 1727–1730.

    Article  PubMed  Google Scholar 

  48. Vulliet, P. R., et al. (2004). Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet, 363(9411), 783–784.

    Article  PubMed  Google Scholar 

  49. Hoshino, K., et al. (2006). Three catheter-based strategies for cardiac delivery of therapeutic gelatin microspheres. Gene Therapy, 13(18), 1320–1327.

    Article  PubMed  CAS  Google Scholar 

  50. Menasche, P., et al. (2001). Myoblast transplantation for heart failure. Lancet, 357(9252), 279–280.

    Article  PubMed  CAS  Google Scholar 

  51. Ben-Haim, S. A., et al. (1996). Nonfluoroscopic, in vivo navigation and mapping technology. Nature Medicine, 2(12), 1393–1395.

    Article  PubMed  CAS  Google Scholar 

  52. Gepstein, L., Hayam, G., & Ben-Haim, S. A. (1997). A novel method for nonfluoroscopic catheter-based electroanatomical mapping of the heart. In vitro and in vivo accuracy results. Circulation, 95(6), 1611–1622.

    PubMed  CAS  Google Scholar 

  53. Fuchs, S., Battler, A., & Kornowski, R. (2007). Catheter-based stem cell and gene therapy for refractory myocardial ischemia. Nature Clinical Practise Cardiovascular Medicine, 4(Suppl 1), S89–S95.

    Article  CAS  Google Scholar 

  54. Thompson, C. A., et al. (2003). Percutaneous transvenous cellular cardiomyoplasty: a novel nonsurgical approach for myocardial cell transplantation. Journal of the American College of Cardiology, 41(11), 1964–1971.

    Article  PubMed  Google Scholar 

  55. Siminiak, T., et al. (2005). Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial. European Heart Journal, 26(12), 1188–1195.

    Article  PubMed  Google Scholar 

  56. Losordo, D. W., et al. (2007). Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation, 115(25), 3165–3172.

    Article  PubMed  Google Scholar 

  57. Deglurkar, I., et al. (2006). Mechanical and electrical effects of cell-based gene therapy for ischemic cardiomyopathy are independent. Human Gene Therapy, 17(11), 1144–1151.

    Article  PubMed  CAS  Google Scholar 

  58. Fouts, K., et al. (2006). Electrophysiological consequence of skeletal myoblast transplantation in normal and infarcted canine myocardium. Heart Rhythm, 3(4), 452–461.

    Article  PubMed  Google Scholar 

  59. Fukushima, S., et al. (2007). Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in a rat chronic ischemic heart failure model. Circulation, 115(17), 2254–2261.

    Article  PubMed  Google Scholar 

  60. Beeres, S. L., et al. (2007). Electrophysiological and arrhythmogenic effects of intramyocardial bone marrow cell injection in patients with chronic ischemic heart disease. Heart Rhythm, 4(3), 257–265.

    Article  PubMed  Google Scholar 

  61. Reinecke, H., et al. (2000). Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. Journal of Cell Biology, 149(3), 731–740.

    Article  PubMed  CAS  Google Scholar 

  62. Bel, A., et al. (2003). Transplantation of autologous fresh bone marrow into infarcted myocardium: a word of caution. Circulation, 108(90101), 247–252.

    Article  Google Scholar 

  63. Menasche, P. (2009). Stem cell therapy for heart failure: are arrhythmias a real safety concern? Circulation, 119(20), 2735–2740.

    Article  PubMed  Google Scholar 

  64. Tran, N., et al. (2006). Short-term heart retention and distribution of intramyocardial delivered mesenchymal cells within necrotic or intact myocardium. Cell Transplantation, 15(4), 351–358.

    Article  PubMed  Google Scholar 

  65. Teng, C. J., et al. (2006). Massive mechanical loss of microspheres with direct intramyocardial injection in the beating heart: implications for cellular cardiomyoplasty. Journal of Thoracic and Cardiovascular Surgery, 132(3), 628–632.

    Article  PubMed  Google Scholar 

  66. Grossman, P. M., et al. (2002). Incomplete retention after direct myocardial injection. Catheter Cardiovasc Interv, 55(3), 392–397.

    Article  PubMed  Google Scholar 

  67. Smits, P. C., et al. (2003). Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. Journal of the American College of Cardiology, 42(12), 2063–2069.

    Article  PubMed  Google Scholar 

  68. Fuchs, S., et al. (2006). Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease. American Journal of Cardiology, 97(6), 823–829.

    Article  PubMed  Google Scholar 

  69. Perin, E. C., et al. (2003). Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation, 107(18), 2294–2302.

    Article  PubMed  Google Scholar 

  70. Baldazzi F et al. (2008) Release of biomarkers of myocardial damage after direct intramyocardial injection of genes and stem cells via the percutaneous transluminal route. European Heart Journal, 29(15), 1819–1826

    Google Scholar 

  71. Mohl, W. (1987). Retrograde cardioplegia via the coronary sinus. Annales Chirurgiae et Gynaecologiae, 76(1), 61–67.

    PubMed  CAS  Google Scholar 

  72. Mohl, W. (1988). The momentum of coronary sinus interventions clinically. Circulation, 77(1), 6–12.

    PubMed  CAS  Google Scholar 

  73. Hessel, E. A., II, & Edmunds, L. H., Jr. (2003). Extracorporeal circulation: perfusion systems. In L. H. Cohn & L. H. Edmunds Jr. (Eds.), Cardiac surgery in the adult (pp. 317–338). New York: McGraw-Hill.

    Google Scholar 

  74. Allen, B. S., et al. (1995). Retrograde cardioplegia does not adequately perfuse the right ventricle. Journal of Thoracic and Cardiovascular Surgery, 109(6), 1116–1124. discussion 1124–6.

    Article  PubMed  CAS  Google Scholar 

  75. Mariani, J. A., et al. (2006). Cardiac resynchronisation therapy for heart failure. Internal Medicine Journal, 36(2), 114–123.

    Article  PubMed  CAS  Google Scholar 

  76. Boekstegers, P., & Kupatt, C. (2004). Current concepts and applications of coronary venous retroinfusion. Basic Research in Cardiology, 99(6), 373–381.

    Article  PubMed  Google Scholar 

  77. von Degenfeld, G., et al. (2003). Selective pressure-regulated retroinfusion of fibroblast growth factor-2 into the coronary vein enhances regional myocardial blood flow and function in pigs with chronic myocardial ischemia. Journal of the American College of Cardiology, 42(6), 1120–1128.

    Article  CAS  Google Scholar 

  78. Fearon, W. F., et al. (2004). Evaluation of high-pressure retrograde coronary venous delivery of FGF-2 protein. Catheterization and Cardiovascular Interventions, 61(3), 422–428.

    Article  PubMed  Google Scholar 

  79. Suzuki, K., et al. (2004). Targeted cell delivery into infarcted rat hearts by retrograde intracoronary infusion: distribution, dynamics, and influence on cardiac function. Circulation, 110(11 Suppl 1), 225–230.

    Google Scholar 

  80. Raake, P., et al. (2004). Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins: comparison with surgical and percutaneous intramyocardial gene delivery. Journal of the American College of Cardiology, 44(5), 1124–1129.

    Article  PubMed  CAS  Google Scholar 

  81. Raake, P. W., et al. (2008). Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors. Gene Therapy, 15(1), 12–17.

    Article  PubMed  CAS  Google Scholar 

  82. Spodick, D. H. (2000). Intrapericardial therapeutics and diagnostics. American Journal of Cardiology, 85(8), 1012–1014.

    Article  PubMed  CAS  Google Scholar 

  83. Tio, R. A., et al. (2002). Thoracoscopic monitoring for pericardial application of local drug or gene therapy. International Journal of Cardiology, 82(2), 117–121.

    Article  PubMed  Google Scholar 

  84. Lamping, K. G., et al. (1997). Intrapericardial administration of adenovirus for gene transfer. American Journal of Physiology-Heart and Circulatory Physiology, 272(1 Part 2), H310–H317.

    CAS  Google Scholar 

  85. Lazarous, D. F., et al. (1999). Adenoviral-mediated gene transfer induces sustained pericardial VEGF expression in dogs: effect on myocardial angiogenesis. Cardiovascular Research, 44(2), 294–302.

    Article  PubMed  CAS  Google Scholar 

  86. Fromes, Y., et al. (1999). Gene delivery to the myocardium by intrapericardial injection. Gene Therapy, 6(4), 683–688.

    Article  PubMed  CAS  Google Scholar 

  87. Davidson, M. J., et al. (2001). Cardiac gene delivery with cardiopulmonary bypass. Circulation, 104(2), 131–133.

    PubMed  CAS  Google Scholar 

  88. Bridges, C. R., et al. (2002). Global cardiac-specific transgene expression using cardiopulmonary bypass with cardiac isolation. Annals of Thoracic Surgery, 73(6), 1939–1946.

    Article  PubMed  Google Scholar 

  89. Bridges, C. R., et al. (2005). Efficient myocyte gene delivery with complete cardiac surgical isolation in situ. Journal of Thoracic and Cardiovascular Surgery, 130(5), 1364.

    Article  PubMed  Google Scholar 

  90. Hayase, M., et al. (2005). Catheter-based antegrade intracoronary viral gene delivery with coronary venous blockade. American Journal of Physiology-Heart and Circulatory Physiology, 288(6), H2995–H3000.

    Article  PubMed  CAS  Google Scholar 

  91. Brunskill, S. J., et al. (2009). Route of delivery and baseline left ventricular ejection fraction, key factors of bone-marrow-derived cell therapy for ischaemic heart disease. European Journal of Heart Failure, 11(9), 887–896.

    Article  PubMed  Google Scholar 

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Acknowledgments

J.M. was supported by a joint NHMRC and NHFA Postgraduate Medical Scholarship. D.K. is supported by an NHMRC Program Grant and NHMRC Research Fellowship.

Disclosure

D.K. is a founder and stockholder in Osprey Medical Inc, which is developing the recirculating system for cardiac gene delivery.

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  1. Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St. Kilda Rd Central, Melbourne, Victoria, 8008, Australia

    Justin A. Mariani & David M. Kaye

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  1. Justin A. Mariani
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Correspondence to David M. Kaye.

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Mariani, J.A., Kaye, D.M. Delivery of Gene and Cellular Therapies for Heart Disease. J. of Cardiovasc. Trans. Res. 3, 417–426 (2010). https://doi.org/10.1007/s12265-010-9190-x

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