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:

AAV Serotype-1 mediates early onset of gene expression in mouse hearts and results in better therapeutic effect

Gene Therapy volume 13, pages 1495–1502 (2006)Cite this article

Abstract

Adeno-associated viral vectors (AAV) are attractive tool for gene therapy for coronary artery disease. However, gene expression in myocardium mediated by AAV serotype 2 (AAV2) does not peak until 4–6 weeks after gene transfer. This delayed gene expression may reduce its therapeutic potential for acute cardiac infarction. To determine whether earlier gene expression and better therapeutic effect could be achieved using a different serotype, CMV promoter driving the EPO gene (AAV-EPO) was packaged into AAV serotypes 1–5 capsids and injected into mouse myocardium. EPO expression was studied by measuring the hematocrits and EPO mRNA. After we found that AAV1 mediates the highest gene expression after 4 days of gene transduction, AAV-LacZ (CMV promoter driving LacZ gene expression) and MLCVEGF (hypoxia-inducible and cardiac-specific VEGF expression) were packaged into AAV1 and 2 capsids. LacZ expression was detected in AAV1-LacZ but not in AAV2-LacZ-injected hearts 1 day after vector injection. Compared to AAV2-MLCVEGF that mediated no significant VEGF expression, AAV1-MLCVEGF mediated 13.7-fold induction of VEGF expression in ischemic hearts 4 days after gene transduction and resulted in more neovasculatures, better cardiac function and less myocardial fibrosis. Thus, AAV1 mediates earlier and higher transgene expression in myocardium and better therapeutic effects.

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
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Berns KI, Linden RM . The cryptic life style of adeno-associated virus. Bioessays 1995; 17: 237–245.

    Article  CAS  PubMed  Google Scholar 

  2. Vassalli G, Bueler H, Dudler J, von Segesser LK, Kappenberger L . Adeno-associated virus (AAV) vectors achieve prolonged transgene expression in mouse myocardium and arteries in vivo: a comparative study with adenovirus vectors. Int J Cardiol 2003; 90: 229–238.

    Article  PubMed  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. Kaplitt MG, Xiao X, Samulski RJ, Li J, Ojamaa K, Klein IL et al. Long-term gene transfer in porcine myocardium after coronary infusion of an adeno-associated virus vector. Ann Thorac Surg 1996; 62: 1669–1676.

    Article  CAS  PubMed  Google Scholar 

  5. Wright MJ, Wightman LM, Lilley C, de Alwis M, Hart SL, Miller A et al. In vivo myocardial gene transfer: optimization, evaluation and direct comparison of gene transfer vectors. Basic Res Cardiol 2001; 96: 227–236.

    Article  CAS  PubMed  Google Scholar 

  6. Su H, Lu R, Kan YW . Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart. Proc Natl Acad Sci USA 2000; 97: 13801–13806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Su H, Arakawa-Hoyt J, Kan YW . Adeno-associated viral vector-mediated hypoxia response element-regulated gene expression in mouse ischemic heart model. Proc Natl Acad Sci USA 2002; 99: 9480–9485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Agrawal RS, Muangman S, Layne MD, Melo L, Perrella MA, Lee RT et al. Pre-emptive gene therapy using recombinant adeno-associated virus delivery of extracellular superoxide dismutase protects heart against ischemic reperfusion injury, improves ventricular function and prolongs survival. Gene Therapy 2004; 11: 962–969.

    Article  CAS  PubMed  Google Scholar 

  10. 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  PubMed  Google Scholar 

  11. Jennings RB, Murry CE, Steenbergen Jr C, Reimer KA . Development of cell injury in sustained acute ischemia. Circulation 1990; 82: II2–II12.

    CAS  PubMed  Google Scholar 

  12. Xiao W, Chirmule N, Berta SC, McCullough B, Gao G, Wilson JM . Gene therapy vectors based on adeno-associated virus type 1. J Virol 1999; 73: 3994–4003.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Muramatsu S, Mizukami H, Young NS, Brown KE . Nucleotide sequencing and generation of an infectious clone of adeno-associated virus 3. Virology 1996; 221: 208–217.

    Article  CAS  PubMed  Google Scholar 

  14. Chiorini JA, Yang L, Liu Y, Safer B, Kotin RM . Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J Virol 1997; 71: 6823–6833.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Chiorini JA, Kim F, Yang L, Kotin RM . Cloning and characterization of adeno-associated virus type 5. J Virol 1999; 73: 1309–1319.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Rutledge EA, Halbert CL, Russell DW . Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol 1998; 72: 309–319.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 USA 2002; 99: 11854–11859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Weber M, Rabinowitz J, Provost N, Conrath H, Folliot S, Briot D et al. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol Ther 2003; 7: 774–781.

    Article  CAS  PubMed  Google Scholar 

  19. Zabner J, Seiler M, Walters R, Kotin RM, Fulgeras W, Davidson BL et al. Adeno-associated virus type 5 (AAV5) but not AAV2 binds to the apical surfaces of airway epithelia and facilitates gene transfer. J Virol 2000; 74: 3852–3858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Davidson BL, Stein CS, Heth JA, Martins I, Kotin RM, Derksen TA et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc Natl Acad Sci USA 2000; 97: 3428–3432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chao H, Liu Y, Rabinowitz J, Li C, Samulski RJ, Walsh CE . Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol Ther 2000; 2: 619–623.

    Article  CAS  PubMed  Google Scholar 

  22. Chao H, Monahan PE, Liu Y, Samulski RJ, Walsh CE . Sustained and complete phenotype correction of hemophilia B mice following intramuscular injection of AAV1 serotype vectors. Mol Ther 2001; 4: 217–222.

    Article  CAS  PubMed  Google Scholar 

  23. Duan D, Yan Z, Yue Y, Ding W, Engelhardt JF . Enhancement of muscle gene delivery with pseudotyped adeno-associated virus type 5 correlates with myoblast differentiation. J Virol 2001; 75: 7662–7671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Du L, Kido M, Lee DV, Rabinowitz JE, Samulski RJ, Jamieson SW et al. Differential myocardial gene delivery by recombinant serotype-specific adeno-associated viral vectors. Mol Ther 2004; 10: 604–608.

    Article  CAS  PubMed  Google Scholar 

  25. Kawamoto S, Shi Q, Nitta Y, Miyazaki J, Allen MD . Widespread and early myocardial gene expression by adeno-associated virus vector type 6 with a beta-actin hybrid promoter. Mol Ther 2005; 11: 980–985.

    Article  CAS  PubMed  Google Scholar 

  26. Wang GL, Jiang BH, Rue EA, Semenza GL . Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92: 5510–5514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang GL, Semenza GL . Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270: 1230–1237.

    Article  CAS  PubMed  Google Scholar 

  28. Jiang BH, Rue E, Wang GL, Roe R, Semenza GL . Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 1996; 271: 17771–17778.

    Article  CAS  PubMed  Google Scholar 

  29. Chavez JC, Agani F, Pichiule P, LaManna JC . Expression of hypoxia-inducible factor-1alpha in the brain of rats during chronic hypoxia. J Appl Physiol 2000; 89: 1937–1942.

    Article  CAS  PubMed  Google Scholar 

  30. Ferrari FK, Samulski T, Shenk T, Samulski RJ . Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol 1996; 70: 3227–3234.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Vincent-Lacaze N, Snyder RO, Gluzman R, Bohl D, Lagarde C, Danos O . Structure of adeno-associated virus vector DNA following transduction of the skeletal muscle. J Virol 1999; 73: 1949–1955.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Burger C, Gorbatyuk OS, Velardo MJ, Peden CS, Williams P, Zolotukhin S et al. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol Ther 2004; 10: 302–317.

    Article  CAS  PubMed  Google Scholar 

  33. Lipshutz GS, Titre D, Brindle M, Bisconte AR, Contag CH, Gaensler KM . Comparison of gene expression after intraperitoneal delivery of AAV2 or AAV5 in utero. Mol Ther 2003; 8: 90–98.

    Article  CAS  PubMed  Google Scholar 

  34. Passini MA, Watson DJ, Vite CH, Landsburg DJ, Feigenbaum AL, Wolfe JH . Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of beta-glucuronidase-deficient mice. J Virol 2003; 77: 7034–7040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rabinowitz JE, Bowles DE, Faust SM, Ledford JG, Cunningham SE, Samulski RJ . Cross-dressing the virion: the transcapsidation of adeno-associated virus serotypes functionally defines subgroups. J Virol 2004; 78: 4421–4432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 2002; 76: 791–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Blankinship MJ, Gregorevic P, Allen JM, Harper SQ, Harper H, Halbert CL et al. Efficient transduction of skeletal muscle using vectors based on adeno-associated virus serotype 6. Mol Ther 2004; 10: 671–678.

    Article  CAS  PubMed  Google Scholar 

  38. Wang Z, Zhu T, Qiao C, Zhou L, Wang B, Zhang J et al. Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat Biotechnol 2005; 23: 321–328.

    Article  CAS  PubMed  Google Scholar 

  39. Summerford C, Samulski RJ . Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 1998; 72: 1438–1445.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Hauck B, Xiao W . Characterization of tissue tropism determinants of adeno-associated virus type 1. J Virol 2003; 77: 2768–2774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen S, Kapturczak M, Loiler SA, Zolotukhin S, Glushakova OY, Madsen KM et al. Efficient transduction of vascular endothelial cells with recombinant adeno-associated virus serotype 1 and 5 vectors. Hum Gene Ther 2005; 16: 235–247.

    Article  CAS  PubMed  Google Scholar 

  42. Luo Z, Diaco M, Murohara T, Ferrara N, Isner JM, Symes JF . Vascular endothelial growth factor attenuates myocardial ischemia-reperfusion injury. Ann Thorac Surg 1997; 64: 993–998.

    Article  CAS  PubMed  Google Scholar 

  43. Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ et al. Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest 1997; 99: 2625–2634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Eriksson U, Alitalo K . VEGF receptor 1 stimulates stem-cell recruitment and new hope for angiogenesis therapies. Nat Med 2002; 8: 775–777.

    Article  CAS  PubMed  Google Scholar 

  45. Markkanen JE, Rissanen TT, Kivela A, Yla-Herttuala S . Growth factor-induced therapeutic angiogenesis and arteriogenesis in the heart–gene therapy. Cardiovasc Res 2005; 65: 656–664.

    Article  CAS  PubMed  Google Scholar 

  46. Matsushita T, Elliger S, Elliger C, Podsakoff G, Villarreal L, Kurtzman GJ et al. Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Therapy 1998; 5: 938–945.

    Article  CAS  PubMed  Google Scholar 

  47. Ishizaka S, Sievers RE, Zhu BQ, Rodrigo MC, Joho S, Foster E et al. New technique for measurement of left ventricular pressure in conscious mice. Am J Physiol Heart Circ Physiol 2004; 286: H1208–H1215.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a National Institutes of Health Grant, HL67969 (YWK) and in part a grant from the Wayne and Gladys Valley Foundation (WG). We thank Dr Xiao Xiao for providing us the AAV serotypes 1, 3, 4 and 5 capsid plasmids.

Author information

Authors and Affiliations

  1. Cardiovascular Research Institute, University of California, San Francisco, CA, USA

    H Su, Y Huang, J Arakawa-Hoyt, W Grossman & Y W Kan

  2. Cardiology Division, University of California, San Francisco, CA, USA

    J Takagawa, J Ye & W Grossman

  3. Department of Laboratory Medicine, University of California, San Francisco, CA, USA

    A Barcena & Y W Kan

Authors
  1. H Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Takagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Barcena
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Arakawa-Hoyt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W Grossman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y W Kan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Su.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Su, H., Huang, Y., Takagawa, J. et al. AAV Serotype-1 mediates early onset of gene expression in mouse hearts and results in better therapeutic effect. Gene Ther 13, 1495–1502 (2006). https://doi.org/10.1038/sj.gt.3302787

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302787

Keywords

This article is cited by

Search

Advanced search

Quick links