Skip to main content
SpringerLink
Log in

Gene Therapy to Create Biological Pacemakers

  • Chapter
Biopacemaking

Part of the book series: Series in Biomedical Engineering ((BIOMENG))

  • 503 Accesses

Abstract

Old age and a variety of cardiovascular disorders may disrupt normal sinus node function. Currently, this is successfully treated with electronic pacemakers, which, however, leave room for improvement. During the past decade, different strategies to initiate pacemaker function by gene therapy were developed. In the search for a biological pacemaker, various approaches were explored, including β 2-adrenergic receptor overexpression, down regulation of the inward rectifier current, and overexpression of the pacemaker current. The most recent advances include overexpression of bioengineered ion channels and genetically modified stem cells. This review considers the strengths and the weaknesses of the different approaches and discusses some of the different viral vectors currently used.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Azene EM, Xue T, Marbán E, Tomaselli GF, Li RA (2005) Non-equilibrium behavior of HCN channels: insights into the role of HCN channels in native and engineered pacemakers. Cardiovasc Res 67:263–273

    Article  Google Scholar 

  2. Biel M, Schneider A, Wahl C (2002) Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc Med 12:206–212

    Article  Google Scholar 

  3. Borer JS (2004) Drug insight: if inhibitors as specific heartrate-reducing agents. Nat Clin Pract Cardiovasc Med 1: 103–109

    Article  Google Scholar 

  4. Brenner M (1999) Gene transfer by adenovectors. Blood 94:3965–3967

    Google Scholar 

  5. Bucchi A, Plotnikov AN, Shlapakova I, Danilo P Jr., Kryukova Y, Qu J, Lu Z, Liu H, Pan Z, Potapova I, Ken-knight B, Girouard S, Cohen IS, Brink PR, Robinson RB, Rosen MR (2006) Wild-type and mutant HCN channels in a tandem biological-electronic cardiac pacemaker. Circulation 114:992–999

    Article  Google Scholar 

  6. Dave UP, Jenkins NA, Copeland NG (2004) Gene therapy insertional mutagenesis insights. Science 303:333

    Article  Google Scholar 

  7. DiFrancesco D (2005) Cardiac pacemaker I(f) current and its inhibition by heart ratereducing agents. Curr Med Res Opin 21:1115–1122

    Article  Google Scholar 

  8. Donahue JK, Kikuchi K, Sasano T (2005) Gene therapy for cardiac arrhythmias. Trends Cardiovasc Med 15:219–224

    Article  Google Scholar 

  9. Duan D, Yue Y, Engelhardt JF (2001) Expanding AAV packaging capacity with trans-splicing or overlapping vec-tors: a quantitative comparison. Mol Ther 4:383–391

    Article  Google Scholar 

  10. Edelberg JM, Aird WC, Rosenberg RD (1998) Enhancement of murine cardiac chronotropy by the molecular transfer of the human beta2 adrenergic receptor cDNA. J Clin Invest 101:337–343

    Google Scholar 

  11. Edelberg JM, Huang DT, Josephson ME, Rosenberg RD (2001) Molecular enhancement of porcine cardiac chronotropy. Heart 86:559–562

    Article  Google Scholar 

  12. Fishbein I, Stachelek SJ, Connolly JM, Wilensky RL, Alferiev I, Levy RJ (2005) Site specific gene delivery in the cardiovascular system. J Control Release 109:37–48

    Article  Google Scholar 

  13. Fleury S, Simeoni E, Zuppinger C, Déglon N, von Segesser LK, Kappenberger L, Vassalli G (2003) Multiply attenuated, self-inactivating lentiviral vectors efficiently deliver and ex-press genes for extended periods of time in adult rat cardiomyocytes in vivo. Circulation 107: 2375–2382

    Article  Google Scholar 

  14. Franz WM, Rothmann T, Frey N, Katus HA (1997) Analysis of tissuespecific gene delivery by recombinant adenoviruses containing cardiacspecific promoters. Cardiovasc Res 35:560–566

    Article  Google Scholar 

  15. Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 348:255–256

    Article  Google Scholar 

  16. Heine HL, Leong HS, Rossi FM, McManus BM, Podor TJ (2005) Strategies of conditional gene expression in myocardium: an overview. Methods Mol Med 112:109–154

    Article  Google Scholar 

  17. Kashiwakura Y, Cho HC, Azene E, Marbán E (2005) Creation of a synthetic pacemaker channel. Circulation 112:U147

    Google Scholar 

  18. Kass-Eisler A, Falck-Pedersen E, Alvira M, Rivera J, Buttrick PM, Wittenberg BA, Cipriani L, Leinwand LA (1993) Quantitative determination of adenovirus-mediated gene delivery to rat cardiac myocytes in vitro and in vivo. Proc Natl Acad Sci USA 90:11498–11502

    Article  Google Scholar 

  19. Kass-Eisler A, Falck-Pedersen E, Alvira M, Rivera J, Buttrick PM, Wittenberg BA, Cipriani L, Leinwand LA (1993) Quantitative determination of adenovirus-mediated gene delivery to rat cardiac myocytes in vitro and in vivo. Proc Natl Acad Sci USA 90:11498–11502

    Article  Google Scholar 

  20. Kehat I, Khimovich L, Caspi O, Gepstein A, Shofti R, Arbel G, Huber I, Satin J, Itskovitz-Eldor J, Gepstein L (2004) Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 22:1282–1289

    Article  Google Scholar 

  21. Kikuchi K, McDonald AD, Sasano T, Donahue JK (2005) Targeted modification of atrial electrophysiology by homogeneous transmural atrial gene transfer. Circulation 111:264–270

    Article  Google Scholar 

  22. Kirshenbaum LA, MacLellan WR, Mazur W, French BA, Schneider MD (1993) Highly efficient gene transfer into adult ventricular myocytes by recombinant adenovirus. J Clin Invest 92:381–387

    Article  Google Scholar 

  23. Kolossov E, Lu Z, Drobinskaya I, Gassanov N, Duan Y, Sauer H, Manzke O, Bloch W, Bohlen H, Hescheler J, Fleischmann BK (2005) Identification and characterization of embryonic stem cell-derived pacemaker and atrial cardiomyocytes. FASEB J 19:577–579

    Google Scholar 

  24. Kyriakou CA, Yong KL, Benjamin R, Pizzey A, Dogan A, Singh N, Davidoff AM, Nathwani AC (2005) Human mesenchymal stem cells (hMSCs) expressing truncated soluble vascular endothelial growth factor receptor (tsFlk-1) following lentiviral-mediated gene transfer inhibit growth of Burkitt’s lymphoma in a murine model. J Gene Med

    Google Scholar 

  25. Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AM, Deans R, Marshak DR, Flake AW (2000) Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 6:1282–1286

    Article  Google Scholar 

  26. Miake J, Marbán E, Nuss HB (2002) Biological pacemaker created by gene transfer. Nature 419:132–133

    Article  Google Scholar 

  27. Miake J, Marbán E, Nuss HB (2003) Functional role of in-ward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J Clin Invest 111:1529–1536

    Article  Google Scholar 

  28. Michels G, Er F, Khan I, Sudkamp M, Herzig S, Hoppe UC (2005) Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias. Circulation 111:399–404

    Article  Google Scholar 

  29. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D (2006) Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 354:151–157

    Article  Google Scholar 

  30. Mistrik P, Mader R, Michalakis S, Weidinger M, Pfeifer A, Biel M (2005) The murine HCN3 gene encodes a hyperpo-larization-activated cation channel with slow kinetics and unique response to cyclic nucleotides. J Biol Chem 280:27056–27061

    Article  Google Scholar 

  31. Miyoshi H, Blomer U, Takahashi M, Gage FH, Verma IM (1998) Development of a self-inactivating lentivirus vector. J Virol 72:8150–8157

    Google Scholar 

  32. Muller OJ, Leuchs B, Pleger ST, Grimm D, Franz WM, Katus HA, Kleinschmidt JA (2006) Improved cardiac gene transfer by transcriptional and transductional targeting of adeno-associated viral vectors. Cardiovasc Res

    Google Scholar 

  33. Plotnikov AN, Sosunov EA, Qu J, Shlapakova IN, Anyukhovsky EP, Liu L, Janse MJ, Brink PR, Cohen IS, Robinson RB, Danilo P Jr, Rosen MR (2004) Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 109:506–512

    Article  Google Scholar 

  34. Potapova I, Plotnikov A, Lu Z, Danilo P Jr, Valiunas V, Qu J, Doronin S, Zuckerman J, Shlapakova IN, Gao J, Pan Z, Herron AJ, Robinson RB, Brink PR, Rosen MR, Cohen IS (2004) Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ Res 94:952–959

    Article  Google Scholar 

  35. Qu J, Barbuti A, Protas L, Santoro B, Cohen IS, Robinson RB (2001) HCN2 overexpression in newborn and adult ventricular myocytes: distinct effects on gating and excitability. Circ Res 89:E8–E14

    Google Scholar 

  36. Qu J, Plotnikov AN, Danilo P Jr., Shlapakova I, Cohen IS, Robinson RB, Rosen MR (2003) Expression and function of a biological pacemaker in canine heart. Circulation 107:1106–1109

    Article  Google Scholar 

  37. Robinson RB, Rosen MR, Brink PR, Cohen IS (2005) Letter regarding the article by Xue et al, “Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes”. Circulation 112:e82–e8

    Article  Google Scholar 

  38. Rosen MR (2005) 15th annual Gordon K. Moe Lecture. Biological pacemaking: in our lifetime? Heart Rhythm 2:418–428

    Article  Google Scholar 

  39. Rosen MR, Brink PR, Cohen IS, Robinson RB (2004) Genes, stem cells and biological pacemakers. Cardiovasc Res 64:12–23

    Article  Google Scholar 

  40. Rosen MR, Robinson RB, Brink P, Cohen IS (2004) Recreating the biological pacemaker. Anat Rec A Discov Mol Cell Evol Biol 280:1046–1052

    Article  Google Scholar 

  41. Seifert R, Scholten A, Gauss R, Mincheva A, Lichter P, Kaupp UB (1999) Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Proc Natl Acad Sci USA 96:9391–9396

    Article  Google Scholar 

  42. Shi W, Wymore R, Yu H, Wu J, Wymore RT, Pan Z, Robinson RB, Dixon JE, McKinnon D, Cohen IS (1999) Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res 85:e1–e6

    Google Scholar 

  43. Srivastava D, Ivey KN (2006) Potential of stem-cell-based therapies for heart disease. Nature 441:1097–1099

    Article  Google Scholar 

  44. Stieber J, Thomer A, Much B, Schneider A, Biel M, Hofmann F (2003) Molecular basis for the different activation kinetics of the pacemaker channels HCN2 and HCN4. J Biol Chem 278:33672–33680

    Article  Google Scholar 

  45. Su H, Joho S, Huang Y, Barcena A, Arakawa-Hoyt J, Grossman W, Kan YW (2004) Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts. Proc Natl Acad Sci USA 101:16280–16285

    Article  Google Scholar 

  46. Tan HL, Hou CJ, Lauer MR, Sung RJ (1995) Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 122:701–714

    Google Scholar 

  47. Tang YL, Tang Y, Zhang YC, Qian K, Shen L, Phillips MI (2005) Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol 46:1339–1350

    Article  Google Scholar 

  48. Thornton AS, Jordaens LJ (2006) Remote magnetic navigation for mapping and ablating right ventricular outflow tract tachycardia. Heart Rhythm 3:691–696

    Article  Google Scholar 

  49. Toro R, Saadi I, Kuburas A, Nemer M, Russo AF (2004) Cell-specific activation of the atrial natriuretic factor promoter by PITX2 and MEF2A. J Biol Chem 279:52087–52094

    Article  Google Scholar 

  50. Totsugawa T, Kobayashi N, Okitsu T, Noguchi H, Watanabe T, Matsumura T, Maruyama M, Fujiwara T, Sakaguchi M, Tanaka N (2002) Lentiviral transfer of the LacZ gene into human endothelial cells and human bone marrow mesenchymal stem cells. Cell Transplant 11:481–488

    Google Scholar 

  51. Tripathy SK, Black HB, Goldwasser E, Leiden JM (1996) Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med 2:545–550

    Article  Google Scholar 

  52. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R (2002) Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 110:381–388

    Article  Google Scholar 

  53. Verma IM, Weitzman MD (2005) Gene therapy: twenty-first century medicine. Annu Rev Biochem 74:711–738

    Article  Google Scholar 

  54. Xue T, Cho HC, Akar FG, Tsang SY, Jones SP, Marbán E, Tomaselli GF, Li RA (2005) Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation 111:11–20

    Article  Google Scholar 

  55. Yellen BB, Forbes ZG, Halverson DS, Fridman G, Barbee KA, Chorny M, Levy R, Friedman G (2005) Targeted drug delivery to magnetic implants for therapeutic applications. J Magn Magn Mater 293:647–654

    Article  Google Scholar 

  56. Zhang L, Benson DW, Tristani-Firouzi M, Ptacek LJ, Tawil R, Schwartz PJ, George AL, Horie M, Andelfinger G, Snow GL, Fu YH, Ackerman MJ, Vincent GM (2005) Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation 111:2720–2726

    Article  Google Scholar 

  57. Zhao J, Pettigrew GJ, Thomas J, Vandenberg JI, Delriviere L, Bolton EM, Carmichael A, Martin JL, Marber MS, Lever AM (2002) Lentiviral vectors for delivery of genes into neonatal and adult ventricular cardiac myocytes in vitro and in vivo. Basic Res Cardiol 97:348–358

    Article  Google Scholar 

  58. Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L, Trono D (1998) Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 72: 9873–9880

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Gerard J. J. Boink, Jacques M. T. de Bakker & Hanno L. Tan

  2. Interuniversity Cardiology Institute Netherlands, Utrecht, The Netherlands

    Gerard J. J. Boink & Jacques M. T. de Bakker

  3. Liver Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Jurgen Seppen

Authors
  1. Gerard J. J. Boink
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jurgen Seppen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jacques M. T. de Bakker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanno L. Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    J. A. E Spaan

  2. Department of Experimental Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Ruben Coronel

  3. Department of Experimental Cardiology Center for Heart Failure Research, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam

    Jacques M. T. de Bakker

  4. The Heart Lung Center, University Medical Center, Utrecht

    Jacques M. T. de Bakker

  5. The Interuniversity Cardiology, Institute of the Netherlands, Utrecht, The Netherlands

    Jacques M. T. de Bakker

  6. Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, 20126, Milano, Italy

    Antonio Zaza

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Boink, G.J.J., Seppen, J., de Bakker, J.M.T., Tan, H.L. (2007). Gene Therapy to Create Biological Pacemakers. In: Spaan, J.A.E., Coronel, R., de Bakker, J.M.T., Zaza, A. (eds) Biopacemaking. Series in Biomedical Engineering. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-72110-9_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-540-72110-9_6

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-72109-3

  • Online ISBN: 978-3-540-72110-9

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics

Search

Navigation