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Prospects for gene transfer for clinical heart failure

Abstract

Congestive heart failure is an inexorable disease associated with unacceptably high morbidity and mortality. Preclinical results indicate that gene transfer using various proteins is a safe and effective approach for increasing function of the failing heart. In the current review, we provide a summary of cardiac gene transfer in general and summarize findings using adenylyl cyclase 6 as therapeutic gene in the failing heart. We also discuss the potential usefulness of a new treatment for congestive heart failure, paracrine-based gene transfer.

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References

  1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB et al. Executive summary: heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation 2012; 125: 188–197.

    Article  Google Scholar 

  2. Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J, Yawn BP et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004; 292: 344–350.

    Article  CAS  Google Scholar 

  3. Lai NC, Tang T, Gao MH, Saito M, Takahashi T, Roth DM et al. Activation of cardiac adenylyl cyclase expression increases function of the failing ischemic heart in mice. J Am Coll Cardiol 2008; 51: 1490–1497.

    Article  CAS  Google Scholar 

  4. Kawase Y, Ly HQ, Prunier F, Lebeche D, Shi Y, Jin H et al. Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. J Am Coll Cardiol 2008; 51: 1112–1119.

    Article  CAS  Google Scholar 

  5. Pleger ST, Shan C, Ksienzyk J, Bekeredjian R, Boekstegers P, Hinkel R et al. Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model. Sci Transl Med 2011; 3: 92ra64.

    Article  CAS  Google Scholar 

  6. Raake PW, Schlegel P, Ksienzyk J, Reinkober J, Barthelmes J, Schinkel S et al. AAV6.betaARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model. Eur Heart J 2012 (in press).

  7. Kaye DM, Preovolos A, Marshall T, Byrne M, Hoshijima M, Hajjar R et al. Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals. J Am Coll Cardiol 2007; 50: 253–260.

    Article  CAS  Google Scholar 

  8. Raake PW, Tscheschner H, Reinkober J, Ritterhoff J, Katus HA, Koch WJ et al. Gene therapy targets in heart failure: the path to translation. Clin Pharmacol Ther 2011; 90: 542–553.

    Article  CAS  Google Scholar 

  9. McKirnan M, Lai N, Waldman L, Dalton N, Guo X, Roth D et al. Intracoronary gene transfer of fibroblast growth factor-4 increases regional contractile function and responsiveness to adrenergic stimulation in heart failure. Card Vasc Regen 2000; 1: 11–21.

    Google Scholar 

  10. Leotta E, Patejunas G, Murphy G, Szokol J, McGregor L, Carbray J et al. Gene therapy with adenovirus-mediated myocardial transfer of vascular endothelial growth factor 121 improves cardiac performance in a pacing model of congestive heart failure. J Thorac Cardiovasc Surg 2002; 123: 1101–1113.

    Article  CAS  Google Scholar 

  11. Lynch P, Lee TC, Fallavollita JA, Canty Jr JM, Suzuki G . Intracoronary administration of AdvFGF-5 (fibroblast growth factor-5) ameliorates left ventricular dysfunction and prevents myocyte loss in swine with developing collaterals and ischemic cardiomyopathy. Circulation 2007; 116: I71–176.

    Article  CAS  Google Scholar 

  12. Vincent KA, Jiang C, Boltje I, Kelly RA . Gene therapy progress and prospects: therapeutic angiogenesis for ischemic cardiovascular disease. Gene Therapy 2007; 14: 781–789.

    Article  CAS  Google Scholar 

  13. Hammond HK, McKirnan MD . Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials. Cardiovasc Res 2001; 49: 561–567.

    Article  CAS  Google Scholar 

  14. Poller W, Hajjar R, Schultheiss HP, Fechner H . Cardiac-targeted delivery of regulatory RNA molecules and genes for the treatment of heart failure. Cardiovasc Res 2011; 86: 353–364.

    Article  Google Scholar 

  15. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 1982; 307: 205–211.

    Article  CAS  Google Scholar 

  16. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991; 325: 1468–1475.

    Article  CAS  Google Scholar 

  17. Engelhardt S, Hein L, Wiesmann F, Lohse MJ . Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice. Proc Natl Acad Sci USA 1999; 96: 7059–7064.

    Article  CAS  Google Scholar 

  18. Engelhardt S, Grimmer Y, Fan GH, Lohse MJ . Constitutive activity of the human beta(1)-adrenergic receptor in beta(1)-receptor transgenic mice. Mol Pharmacol 2001; 60: 712–717.

    CAS  PubMed  Google Scholar 

  19. Raake PW, Vinge LE, Gao E, Boucher M, Rengo G, Chen X et al. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res 2008; 103: 413–422.

    Article  CAS  Google Scholar 

  20. Rengo G, Lymperopoulos A, Zincarelli C, Donniacuo M, Soltys S, Rabinowitz JE et al. Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation 2009; 119: 89–98.

    Article  CAS  Google Scholar 

  21. Volkers M, Weidenhammer C, Herzog N, Qiu G, Spaich K, von Wegner F et al. The inotropic peptide betaARKct improves betaAR responsiveness in normal and failing cardiomyocytes through G(betagamma)-mediated L-type calcium current disinhibition. Circ Res 2011; 108: 27–39.

    Article  Google Scholar 

  22. Brinks H, Boucher M, Gao E, Chuprun JK, Pesant S, Raake PW et al. Level of G protein-coupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms. Circ Res 2010; 107: 1140–1149.

    Article  CAS  Google Scholar 

  23. Lipskaia L, Chemaly ER, Hadri L, Lompre AM, Hajjar RJ . Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. Expert Opin Biol Ther 2010; 10: 29–41.

    Article  CAS  Google Scholar 

  24. Gwathmey JK, Yerevanian AI, Hajjar RJ . Cardiac gene therapy with SERCA2a: from bench to bedside. J Mol Cell Cardiol 2011; 50: 803–812.

    Article  CAS  Google Scholar 

  25. Chen Y, Escoubet B, Prunier F, Amour J, Simonides WS, Vivien B et al. Constitutive cardiac overexpression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase delays myocardial failure after myocardial infarction in rats at a cost of increased acute arrhythmias. Circulation 2004; 109: 1898–1903.

    Article  CAS  Google Scholar 

  26. Lyon AR, Bannister ML, Collins T, Pearce E, Sepehripour AH, Dubb SS et al. SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure. Circ Arrhythm Electrophysiol 2011; 4: 362–372.

    Article  CAS  Google Scholar 

  27. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 2011; 124: 304–313.

    Article  CAS  Google Scholar 

  28. Rohde D, Brinks H, Ritterhoff J, Qui G, Ren S, Most P . S100A1 gene therapy for heart failure: a novel strategy on the verge of clinical trials. J Mol Cell Cardiol 2011; 50: 777–784.

    Article  CAS  Google Scholar 

  29. Lyon AR, Sato M, Hajjar RJ, Samulski RJ, Harding SE . Gene therapy: targeting the myocardium. Heart 2008; 94: 89–99.

    Article  CAS  Google Scholar 

  30. Fleury S, Simeoni E, Zuppinger C, Deglon N, von Segesser LK, Kappenberger L et al. Multiply attenuated, self-inactivating lentiviral vectors efficiently deliver and express genes for extended periods of time in adult rat cardiomyocytes in vivo. Circulation 2003; 107: 2375–2382.

    Article  CAS  Google Scholar 

  31. Roth DM, Lai NC, Gao MH, Drumm JD, Jimenez J, Feramisco JR et al. Indirect intracoronary delivery of adenovirus encoding adenylyl cyclase increases left ventricular contractile function in mice. Am J Physiol Heart Circ Physiol 2004; 287: H172–H177.

    Article  CAS  Google Scholar 

  32. Hammond HK . Intracoronary gene transfer of fibroblast growth factor in experimental and clinical myocardial ischemia. Gene Ther Regul 2002; 1: 325–342.

    Article  CAS  Google Scholar 

  33. French BA, Mazur W, Geske RS, Bolli R . Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation 1994; 90: 2414–2424.

    Article  CAS  Google Scholar 

  34. Kaspar BK, Roth DM, Lai NC, Drumm JD, Erickson DA, McKirnan MD et al. Myocardial gene transfer and long-term expression following intracoronary delivery of adeno-associated virus. J Gene Med 2005; 7: 316–324.

    Article  CAS  Google Scholar 

  35. Inagaki K, Fuess S, Storm TA, Gibson GA, McTiernan CF, Kay MA et al. Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 2006; 14: 45–53.

    Article  CAS  Google Scholar 

  36. Tang T, Lai NC, Roth DM, Drumm J, Guo T, Lee KW et al. Adenylyl cyclase type V deletion increases basal left ventricular function and reduces left ventricular contractile responsiveness to beta-adrenergic stimulation. Basic Res Cardiol 2006; 101: 117–126.

    Article  CAS  Google Scholar 

  37. Tang T, Gao MH, Lai NC, Firth AL, Takahashi T, Guo T et al. Adenylyl cyclase type 6 deletion decreases left ventricular function via impaired calcium handling. Circulation 2008; 117: 61–69.

    Article  CAS  Google Scholar 

  38. Gao M, Ping P, Post S, Insel PA, Tang R, Hammond HK . Increased expression of adenylylcyclase type VI proportionately increases beta-adrenergic receptor-stimulated production of cAMP in neonatal rat cardiac myocytes. Proc Natl Acad Sci USA 1998; 95: 1038–1043.

    Article  CAS  Google Scholar 

  39. Gao MH, Lai NC, Roth DM, Zhou J, Zhu J, Anzai T et al. Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice. Circulation 1999; 99: 1618–1622.

    Article  CAS  Google Scholar 

  40. Gao MH, Bayat H, Roth DM, Yao Zhou J, Drumm J, Burhan J et al. Controlled expression of cardiac-directed adenylylcyclase type VI provides increased contractile function. Cardiovasc Res 2002; 56: 197–204.

    Article  CAS  Google Scholar 

  41. Lai NC, Roth DM, Gao MH, Fine S, Head BP, Zhu J et al. Intracoronary delivery of adenovirus encoding adenylyl cyclase VI increases left ventricular function and cAMP-generating capacity. Circulation 2000; 102: 2396–2401.

    Article  CAS  Google Scholar 

  42. Lai NC, Roth DM, Gao MH, Tang T, Dalton N, Lai YY et al. Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure. Circulation 2004; 110: 330–336.

    Article  CAS  Google Scholar 

  43. D'Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh RA, Liggett SB et al. Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA 1997; 94: 8121–8126.

    Article  CAS  Google Scholar 

  44. Roth DM, Gao MH, Lai NC, Drumm J, Dalton N, Zhou JY et al. Cardiac-directed adenylyl cyclase expression improves heart function in murine cardiomyopathy. Circulation 1999; 99: 3099–3102.

    Article  CAS  Google Scholar 

  45. Roth DM, Bayat H, Drumm JD, Gao MH, Swaney JS, Ander A et al. Adenylyl cyclase increases survival in cardiomyopathy. Circulation 2002; 105: 1989–1994.

    Article  CAS  Google Scholar 

  46. Rebolledo B, Lai NC, Gao MH, Takahashi T, Roth DM, Baird SM et al. Adenylylcyclase gene transfer increases function of the failing heart. Hum Gene Ther 2006; 17: 1043–1048.

    Article  CAS  Google Scholar 

  47. Roth DM, Drumm JD, Bhargava V, Swaney JS, Gao MH, Hammond HK . Cardiac-directed expression of adenylyl cyclase and heart rate regulation. Basic Res Cardiol 2003; 98: 380–387.

    Article  CAS  Google Scholar 

  48. Tang T, Gao MH, Roth DM, Guo T, Hammond HK . Adenylyl cyclase type VI corrects cardiac sarcoplasmic reticulum calcium uptake defects in cardiomyopathy. Am J Physiol Heart Circ Physiol 2004; 287: H1906–H1912.

    Article  CAS  Google Scholar 

  49. Timofeyev V, He Y, Tuteja D, Zhang Q, Roth DM, Hammond HK et al. Cardiac-directed expression of adenylyl cyclase reverses electrical remodeling in cardiomyopathy. J Mol Cell Cardiol 2006; 41: 170–181.

    Article  CAS  Google Scholar 

  50. Takahashi T, Tang T, Lai NC, Roth DM, Rebolledo B, Saito M et al. Increased cardiac adenylyl cyclase expression is associated with increased survival after myocardial infarction. Circulation 2006; 114: 388–396.

    Article  CAS  Google Scholar 

  51. Dai B, Huang W, Xu M, Millard RW, Gao MH, Hammond HK et al. Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function. J Am Coll Cardiol 2011; 58: 2118–2127.

    Article  CAS  Google Scholar 

  52. Solaro RJ . Modulation of cardiac myofilament activity by protein phosphorylation. In: Fozzarad H, Solaro RJ (eds). Handbook of Physiology, Volume 1, The Heart. Oxford University Press: New York, 2002, pp 264–300.

    Google Scholar 

  53. Messer AE, Jacques AM, Marston SB . Troponin phosphorylation and regulatory function in human heart muscle: dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end-stage heart failure. J Mol Cell Cardiol. 2007; 42: 247–259.

    Article  CAS  Google Scholar 

  54. Guellich A, Gao S, Hong C, Yan L, Wagner TE, Dhar SK et al. Effects of cardiac overexpression of type 6 adenylyl cyclase affects on the response to chronic pressure overload. Am J Physiol Heart Circ Physiol 2010; 299: H707–H712.

    Article  CAS  Google Scholar 

  55. Sugano Y, Lai NC, Gao MH, Firth AL, Yuan JX, Lew WY et al. Activated expression of cardiac adenylyl cyclase 6 reduces dilation and dysfunction of the pressure-overloaded heart. Biochem Biophys Res Commun 2011; 405: 349–355.

    Article  CAS  Google Scholar 

  56. Rowe JW, Troen BR . Sympathetic nervous system and aging in man. Endocr Rev 1980; 1: 167–179.

    Article  CAS  Google Scholar 

  57. Tang T, Hammond HK, Firth AL, Yang Y, Gao MH, Yuan JX et al. Adenylyl cyclase 6 improves calcium uptake and LV function in aged hearts. J Am Coll Cardiol 2011; 57: 1846–1855.

    Article  CAS  Google Scholar 

  58. Gao MH, Tang T, Guo T, Sun SQ, Feramisco JR, Hammond HK . Adenylyl cyclase type VI gene transfer reduces phospholamban expression in cardiac myocytes via activating transcription factor 3. J Biol Chem 2004; 279: 38797–38802.

    Article  CAS  Google Scholar 

  59. Gao MH, Miyanohara A, Feramisco JR, Tang T . Activation of PH-domain leucine-rich protein phosphatase 2 (PHLPP2) by agonist stimulation in cardiac myocytes expressing adenylyl cyclase type 6. Biochem Biophys Res Commun 2009; 384: 193–198.

    Article  CAS  Google Scholar 

  60. Gao MH, Tang T, Guo T, Miyanohara A, Yajima T, Pestonjamasp K et al. Adenylyl cyclase type VI increases Akt activity and phospholamban phosphorylation in cardiac myocytes. J Biol Chem 2008; 283: 33527–33535.

    Article  CAS  Google Scholar 

  61. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011; 365: 2357–2365.

    Article  CAS  Google Scholar 

  62. Rivera VM, Gao GP, Grant RL, Schnell MA, Zoltick PW, Rozamus LW et al. Long-term pharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer. Blood 2005; 105: 1424–1430.

    Article  CAS  Google Scholar 

  63. Lai NC, Tang T, Gao MH, Saito M, Miyanohara A, Hammond HK . Improved function of the failing rat heart by regulated expression of insulin-like growth factor I via intramuscular gene transfer. Hum Gene Ther 2012; 23: 255–261.

    Article  CAS  Google Scholar 

  64. Rolain JM, Mallet MN, Raoult D . Correlation between serum doxycycline concentrations and serologic evolution in patients with Coxiella burnetii endocarditis. J Infect Dis 2003; 188: 1322–1325.

    Article  CAS  Google Scholar 

  65. Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 2000; 24: 257–261.

    Article  CAS  Google Scholar 

  66. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342–347.

    Article  CAS  Google Scholar 

  67. O'Callaghan DS, Savale L, Montani D, Jais X, Sitbon O, Simonneau G et al. Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol 2011; 8: 526–538.

    Article  CAS  Google Scholar 

  68. Sastry A, Arnold E, Gurji H, Iwasa A, Bui H, Hassankhani A et al. Cardiac-directed expression of adenylyl cyclase VI facilitates atrioventricular nodal conduction. J Am Coll Cardiol 2006; 48: 559–565.

    Article  CAS  Google Scholar 

  69. Gao MH, Tang T, Miyanohara A, Feramisco JR, Hammond HK . beta(1)-Adrenergic receptor vs adenylyl cyclase 6 expression in cardiac myocytes: differences in transgene localization and intracellular signaling. Cell Signal 2010; 22: 584–589.

    Article  CAS  Google Scholar 

  70. Gao MH, Tang T, Lai NC, Miyanohara A, Guo T, Tang R et al. Beneficial effects of adenylyl cyclase type 6 (AC6) expression persist using a catalytically inactive AC6 mutant. Mol Pharmacol 2011; 79: 381–388.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a Grant-in-Aid from American Heart Association, grants from the National Institute of Health (P01 HL66941, HL088426 and HL081741) and a Merit Review Award from the Department of Veterans Affairs.

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TT, MHG and HKH wrote and approved the final draft of the manuscript.

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Correspondence to H Kirk Hammond.

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Drs Tang and Gao declare no conflict of interest. Dr Hammond is founder, consultant and equity holder in Renova Therapeutics. Renova was not involved in any manner with the studies reviewed.

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Tang, T., Gao, M. & Hammond, H. Prospects for gene transfer for clinical heart failure. Gene Ther 19, 606–612 (2012). https://doi.org/10.1038/gt.2012.36

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