Journal of Cardiac Failure
Volume 14, Issue 5 , Pages 355-367 , June 2008

Design of a Phase 1/2 Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Heart Failure

  • Roger J. Hajjar, MD

      Affiliations

    • Mount Sinai School of Medicine, New York, New York
    • Corresponding Author InformationReprint requests: Roger J. Hajjar, MD, Cardiovascular Research Center, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1030, New York, NY 10029.
  • ,
  • Krisztina Zsebo, PhD

      Affiliations

    • Celladon Corporation, San Diego, California
  • ,
  • Lawrence Deckelbaum

      Affiliations

    • Johnson & Johnson Pharmaceutical Research & Development, LLC, Radnor, PA
  • ,
  • Craig Thompson, MD

      Affiliations

    • Division of Cardiology, Dartmouth College, Hanover, New Hampshire
  • ,
  • Jeff Rudy, MD

      Affiliations

    • Celladon Corporation, San Diego, California
  • ,
  • Alex Yaroshinsky, PhD

      Affiliations

    • Celladon Corporation, San Diego, California
  • ,
  • Hung Ly, MD

      Affiliations

    • Mount Sinai School of Medicine, New York, New York
  • ,
  • Yoshiaki Kawase, MD

      Affiliations

    • Mount Sinai School of Medicine, New York, New York
  • ,
  • Kim Wagner, MA

      Affiliations

    • Celladon Corporation, San Diego, California
  • ,
  • Kenneth Borow, MD

      Affiliations

    • Encorium Group, Inc., Wayne, Pennsylvania
  • ,
  • Brian Jaski, MD

      Affiliations

    • San Diego Cardiac Center/Sharp Hospital, San Diego, California
  • ,
  • Barry London, MD

      Affiliations

    • University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
  • ,
  • Barry Greenberg, MD

      Affiliations

    • University of California at San Diego Medical Center, San Diego, California
  • ,
  • Daniel F. Pauly, MD

      Affiliations

    • Shands Hospital, University of Florida, Gainesville, Florida
  • ,
  • Richard Patten, MD

      Affiliations

    • New England Medical Center, Tufts University, Boston, Massachusetts
  • ,
  • Randall Starling, MD

      Affiliations

    • Cleveland Clinic, Cleveland, Ohio
  • ,
  • Donna Mancini, MD

      Affiliations

    • Columbia University Hospital, New York, New York
  • ,
  • Mariell Jessup, MD

      Affiliations

    • Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania

Received 2 August 2007 ,Revised 5 February 2008 ,Accepted 6 February 2008.

References 

  1. Hunt S, Abraham W, Chin M, Feldman A, Francis G, Ganiats T, et al. Cardiology ACo, Guidelines AHATFoP, Physicians ACoC, Transplantation ISfHaL, Society. HR. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154–e235
  2. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69–e171
  3. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007–2018
  4. Terracciano C, Hardy J, Birks E, Khaghani A, Banner N, Yacoub M. Clinical recovery from end-stage heart failure using left-ventricular assist device and pharmacological therapy correlates with increased sarcoplasmic reticulum calcium content but not with regression of cellular hypertrophy. Circulation. 2004;109:2263–2265
  5. Bers D. Cardiac excitation-contraction coupling. Nature. 2002;415:198–205
  6. MacLennan DH, Kranias EG. Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol. 2003;4:566–577
  7. Gwathmey J, Hajjar R. Relation between steady-state force and intracellular [Ca2+] in intact human myocardium. Index of myofibrillar responsiveness to Ca2+. Circulation. 1990;82:1266–1278
  8. Gwathmey JK, Hajjar RJ. Intracellular calcium related to force development in twitch contraction of mammalian myocardium. Cell Calcium. 1990;11:531–538
  9. Meyer M, Schillinger W, Pieske B, Holubarsch C, Heilmann C, Posival H, et al. Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation. 1995;92:778–784
  10. Schmidt U, Hajjar R, Helm P, Kim C, Doye A, Gwathmey J. Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J Mol Cell Cardiol. 1998;30:1929–1937
  11. del Monte F, Harding S, Schmidt U, Matsui T, Kang Z, Dec G, et al. Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation. 1999;100:2308–2311
  12. del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK, et al. Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca2+-ATPase in a rat model of heart failure. Circulation. 2001;104:1424–1429
  13. Hajjar RJ, Kang JX, Gwathmey JK, Rosenzweig A. Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. [see comment] Circulation. 1997;95:423–429
  14. Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T, et al. Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci U S A. 2000;97:793–798
  15. Sakata S, Lebeche D, Sakata N, Sakata Y, Chemaly E, Liang L, et al. Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model. Am J Physiol Heart Circ Physiol. 2007;292:H1204–H1207
  16. Sakata S, Lebeche D, Sakata N, Sakata Y, Chemaly E, Liang L, et al. Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins. J Mol Cell Cardiol. 2007;42:852–861
  17. Sakata S, Lebeche D, Sakata Y, Sakata N, Chemaly E, Liang L, et al. Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer. Mol Ther. 2006;13:987–996
  18. Lowes B, Gilbert E, Abraham W, Minobe W, Larrabee P, Ferguson D, et al. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med. 2002;346:1357–1365
  19. Stüdeli R, Jung S, Mohacsi P, Perruchoud S, Castiglioni P, Seiler C, et al. Diastolic dysfunction in human cardiac allografts is associated with reduced SERCA2a gene expression. Am J Transplant. 2006;6:775–782
  20. Samulski R. AAV vectors, the future workhorse of human gene therapy. Ernst Schering Res Found Workshop. 2003;43:25–40
  21. Wu Z, Asokan A, Samulski R. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol Ther. 2006;14:316–327
  22. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A. 2002;99:11854–11859
  23. Palomeque J, Chemaly E, Colosi P, Wellman J, Zhou S, Del Monte F, et al. Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo. Gene Ther. 2007;14:1055
  24. Carter PJ, Samulski RJ. Adeno-associated viral vectors as gene delivery vehicles. Int J Molec Med. 2000;6:17–27
  25. Carter B. Adeno-associated virus vectors in clinical trials. Hum Gene Ther. 2005;16:541–550
  26. Stilwell JL, Samulski RJ. Adeno-associated virus vectors for therapeutic gene transfer. Biotechniques. 2003;34:148–150
  27. Manno CS, Pierce G, Arruda V, Glader B, Ragni M, Rasko J, 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
  28. Davidson MJ, Jones JM, Emani SM, Wilson KH, Jaggers J, Koch WJ, et al. Cardiac gene delivery with cardiopulmonary bypass. Circulation. 2001;104:131–133
  29. Guzman RJ, Lemarchand P, Crystal RG, Epstein SE, Finkel T. Efficient gene transfer into myocardium by direct injection of adenovirus vectors. Circ Res. 1993;73:1202–1207
  30. Leor J, Quinones M, Patterson M, Kedes L, Kloner R. Adenovirus-mediated gene transfer into infarcted myocardium: feasibility, timing, and location of expression. J Mol Cell Cardiol. 1996;28:2057–2067
  31. Rosengart T, Lee L, Patel S, Sanborn T, Parikh M, Bergman G, 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. 1999;100:468–474
  32. Rosengart T, Patel S, Crystal R. Therapeutic angiogenesis: protein and gene therapy delivery strategies. Cardiovasc Risk. 1999;6:29–40
  33. Preovolos A, Mennen M, Bilney A, Mariani J, Kaye D, Power J. Development of a novel perfusion technique to allow targeted delivery of gene therapy—the V-Focus system. J Extra Corpor Technol. 2006;38:51–52
  34. Hayase M, Del Monte F, Kawase Y, Macneill BD, McGregor J, Yoneyama R, et al. Catheter-based antegrade intracoronary viral gene delivery with coronary venous blockade. Am J Physiol Heart Circ Physiol. 2005;288:H2995–H3000
  35. Kaye D, 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
  36. Ly H, Kawase Y, Prunier F, Lebeche D, Shi Y, Yoneyama R, et al. Cardiac function improvement following in vivo intracoronary adeno-associated virus type 1 vector gene transfer of SERCA2a in a pre-clinical model of heart failure. Circulation. 2007;116:46
  37. Castillo-Davis C. The evolution of noncoding DNA: how much junk, how much func?. Trends Genet. 2006;21:533–536
  38. Dorn GN, Molkentin J. Manipulating cardiac contractility in heart failure: data from mice and men. Circulation. 2004;109:150–158
  39. Waggoner J, Kranias E. Role of phospholamban in the pathogenesis of heart failure. Heart Failure Clin. 2005;1:207–218
  40. Gianni D, Chan J, Gwathmey JK, del Monte F, Hajjar RJ. SERCA2a in heart failure: role and therapeutic prospects. J Bioenerg Biomembr. 2005;37:375–380
  41. del Monte F, Hajjar R. Targeting calcium cycling proteins in heart failure through gene transfer. Physiology. 2003;546:49–61
  42. del Monte FK, E , Tabchy A, Hajjar R. Targeted gene transfer in heart failure: implications for novel gene identification. Curr Opin Mol Ther. 2004;6:381–394
  43. Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B, Holtz J, et al. Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in failing and nonfailing human myocardium. Circ Res. 1994;75:434–442
  44. Hasenfuss G, Reinecke H, Studer R, Pieske B, Meyer M, Drexler H, et al. Calcium cycling proteins and force-frequency relationship in heart failure. Basic Res Cardiol. 1996;91(Suppl 2):17–22
  45. Reinecke H, Studer R, Vetter R, Just HH, J , Drexler H. Role of the cardiac sarcolemmal Na(+)-Ca2+ exchanger in end-stage human heart failure. Ann N Y Acad Sci. 1996;779:543–545
  46. Studer R, Reinecke H, Bilger J, Eschenhagen T, Böhm M, Hasenfuss G, et al. Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure. Circ Res. 1994;75:443–453
  47. Marx SO, Marks AR. Regulation of the ryanodine receptor in heart failure. Basic Res Cardiol. 2002;97(Suppl 1):I49–I51
  48. del Monte F, Harding SE, Dec GW, Gwathmey JK, Hajjar RJ. Targeting phospholamban by gene transfer in human heart failure. Circulation. 2002;105:904–907
  49. del Monte F, Lebeche D, Guerrero J, Tsuji T, Doye A, Gwathmey J, et al. Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling. Proc Natl Acad Sci U S A. 2004;101:5622–5627
  50. Lipskaia L, del Monte F, Yacoubi S, Hadri L, Hours M, Hajjar R, et al. Sarco/endoplasmic reticulum Ca2+-ATPase gene transfer reduces VSMC proliferation and neointima formation in the rat. Circ Res. 2005;97:488–495
  51. Monahan P, Samulski R. Adeno-associated virus vectors for gene therapy: more pros than cons?. Mol Med Today. 2000;6:433–440
  52. Monahan P, Samulski R, Tazelaar J, Xiao X, Nichols T, Bellinger D, et al. Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia. Gene Ther. 1998;5:40–49
  53. Monahan P, Samulski R. AAV vectors: is clinical success on the horizon?. Gene Therapy. 2000;7:24–30
  54. Jiang H, Pierce G, Ozelo M, de Paula E, Vargas J, Smith P, et al. Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Mol Ther. 2006;14:452–455
  55. Kay M, Manno C, Ragni M, Larson P, Couto L, 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
  56. Bleijs D. Workshop on shedding data from gene therapy studies with viral vectors. J Gene Med. 2004;7:256–259
  57. Meulenberg JM. Immune responses in a lipoprotein lipase deficiency study using AAV-1-LPLS447X immune responses to adeno-associated virus (AAV) vectors, NIH Recombinant DNA Advisory Committee Meeting. Bethesda, MD; 2007.
  58. Mingozzi F, Muelenberg J, Hui D, Basner-Tschakarajn E, de Pos P, High KA. Intramuscular administration of an AAV1 vector in humans results in capsid specific T cell responses. Mol Therapy. Proceedings from the American Society of Gene Therapy 10th Annual Meeting, May 30-June 3, 2007, Seattle, WA.
  59. Kaiser J. Gene therapy. Questions remain on cause of death in arthritis trial. Science. 2007;317:1665
  60. Kaiser J. Clinical research. Death prompts a review of gene therapy vector. Science. 2007;317:580
  61. Boecker W, Bernecker O, Wu J, Zhu X, Sawa T, Grazette L, et al. Cardiac-specific gene expression facilitated by an enhanced myosin light chain promoter. Mol Imaging. 2004;3:69–75

 Sponsored by Celladon Corporation which has supported the manufacture of AAV1/SERCA2a under the trade name MYDICAR. R.J.H. supported in part by grants from the National Institutes of Health: R01 HL078691, HL071763, HL080498, and HL083156, and is a scientific founder of Celladon Corporation (the company financing the trial). K.Z. is CEO of Celladon Corporation.

 L.D. employed by Johnson & Johnson, which has an equity investment in Celladon. K.B. employed by Encorium Inc., which is contracted by Celladon Corporation to conduct the clinical trial. J.R. is an employee and stock owner of Celladon Corporation.

PII: S1071-9164(08)00062-6

doi: 10.1016/j.cardfail.2008.02.005

Journal of Cardiac Failure
Volume 14, Issue 5 , Pages 355-367 , June 2008