Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals

Abstract

Abnormal excitation–contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 × 1010 d.r.p.; medium 1 × 1012 d.r.p. and high 1 × 1013 d.r.p.) in conjunction with an intra-coronary delivery group (2.5 × 1013 d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d tmax; low dose −220±70, P>0.05; medium dose 125±53, P<0.05; high dose 287±104, P<0.05) and echocardiographically (fractional shortening: low dose −3±2, P>0.05; medium dose 1±2, P>0.05; high dose 6.5±3.9, P<0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Hoshijima M, Ikeda Y, Iwanaga Y, Minamisawa S, Date MO, Gu Y et al. Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med 2002; 8: 864–871.

    Article  CAS  Google Scholar 

  2. Melo LG, Agrawal R, Zhang L, Rezvani M, Mangi AA, Ehsan A et al. Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene. Circulation 2002; 105: 602–607.

    Article  CAS  Google Scholar 

  3. Kawada T, Nakazawa M, Nakauchi S, Yamazaki K, Shimamoto R, Urabe M et al. Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters. Proc Natl Acad Sci USA 2002; 99: 901–906.

    Article  CAS  Google Scholar 

  4. del Monte F, Harding SE, Schmidt U, Matsui T, Kang ZB, Dec GW et al. Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 1999; 100: 2308–2311.

    Article  CAS  Google Scholar 

  5. Pacak CA, Mah CS, Thattaliyath BD, Conlon TJ, Lewis MA, Cloutier DE et al. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res 2006; 99: e3–e9.

    Article  CAS  Google Scholar 

  6. Muller OJ, Katus HA, Bekeredjian R . Targeting the heart with gene therapy-optimized gene delivery methods. Cardiovasc Res 2007; 73: 453–462.

    Article  Google Scholar 

  7. Hasenfuss G, Pieske B . Calcium cycling in congestive heart failure. J Mol Cell Cardiol 2002; 34: 951–969.

    Article  CAS  Google Scholar 

  8. Hajjar RJ, Kang JX, Gwathmey JK, Rosenzweig A . Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. Circulation 1997; 95: 423–429.

    Article  CAS  Google Scholar 

  9. 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 Ca(2+)-ATPase in a rat model of heart failure. Circulation 2001; 104: 1424–1429.

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. 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 USA 2000; 97: 793–798.

    Article  CAS  Google Scholar 

  12. Teucher N, Prestle J, Seidler T, Currie S, Elliott EB, Reynolds DF et al. Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening. Circulation 2004; 110: 3553–3559.

    Article  CAS  Google Scholar 

  13. Muller OJ, Leuchs B, Pleger ST, Grimm D, Franz WM, Katus HA et al. Improved cardiac gene transfer by transcriptional and transductional targeting of adeno-associated viral vectors. Cardiovasc Res 2006; 70: 70–78.

    Article  Google Scholar 

  14. Mah C, Cresawn KO, Fraites Jr TJ, Pacak CA, Lewis MA, Zolotukhin I et al. Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. Gene Therapy 2005; 12: 1405–1409.

    Article  CAS  Google Scholar 

  15. 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 

  16. Chu D, Sullivan CC, Weitzman MD, Du L, Wolf PL, Jamieson SW et al. Direct comparison of efficiency and stability of gene transfer into the mammalian heart using adeno-associated virus versus adenovirus vectors. J Thorac Cardiovasc Surg 2003; 126: 671–679.

    Article  CAS  Google Scholar 

  17. 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 

  18. Periasamy M, Reed TD, Liu LH, Ji Y, Loukianov E, Paul RJ et al. Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene. J Biol Chem 1999; 274: 2556–2562.

    Article  CAS  Google Scholar 

  19. Muhlhauser J, Jones M, Yamada I, Cirielli C, Lemarchand P, Gloe TR et al. Safety and efficacy of in vivo gene transfer into the porcine heart with replication-deficient, recombinant adenovirus vectors. Gene Therapy 1996; 3: 145–153.

    CAS  PubMed  Google Scholar 

  20. Donahue JK, Kikkawa K, Johns DC, Marban E, Lawrence JH . Ultrarapid, highly efficient viral gene transfer to the heart. Proc Natl Acad Sci USA 1997; 94: 4664–4668.

    Article  CAS  Google Scholar 

  21. Donahue JK, Kikkawa K, Thomas AD, Marban E, Lawrence JH . Acceleration of widespread adenoviral gene transfer to intact rabbit hearts by coronary perfusion with low calcium and serotonin. Gene Therapy 1998; 5: 630–634.

    Article  CAS  Google Scholar 

  22. Wright MJ, Wightman LM, Latchman DS, Marber MS . In vivo myocardial gene transfer: optimization and evaluation of intracoronary gene delivery in vivo. Gene Therapy 2001; 8: 1833–1839.

    Article  CAS  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. Raake PW, Hinkel R, Muller S, Delker S, Kreuzpointner R, Kupatt C et al. Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors. Gene Therapy 2008; 15: 12–17.

    Article  CAS  Google Scholar 

  25. Fiedler B, Lohmann SM, Smolenski A, Linnemuller S, Pieske B, Schroder F et al. Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes. Proc Natl Acad Sci USA 2002; 99: 11363–11368.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by funding granted by Celladon Corporation, La Jolla, CA, USA, and in part by grants from the National Institutes of Health: R01 HL078691, HL057263, HL071763, HL080498, HL083156 and a Leducq Transatlantic Network (RJH).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M J Byrne.

Additional information

Disclosure

Dr John M Power and Dr David M Kaye are inventors of the V-Focus cardiac recirculation system. Dr Roger Hajjar is a co-founder of Celladon Corporation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Byrne, M., Power, J., Preovolos, A. et al. Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals. Gene Ther 15, 1550–1557 (2008). https://doi.org/10.1038/gt.2008.120

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.120

Keywords

This article is cited by

Search

Quick links