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Efficient and long-term intracardiac gene transfer in δ-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectors

Gene Therapy volume 10, pages 1807–1813 (2003)Cite this article

Abstract

Intracardiac gene transfer and gene therapy have been investigated with different vector systems. Here we used adeno-associated virus (AAV) vectors to deliver either a reporter gene or a therapeutic gene into the heart of golden Syrian hamsters. The method of gene delivery was direct infusion of the AAV2 vectors into the coronary artery ex vivo in a heterotopically transplanted heart. When an AAV2 vector carrying the Lac-Z gene driven by CMV promoter was delivered into the heart of healthy hamsters, effective gene transfer was achieved in up to 90% of the cardiomyocytes. Lac-Z gene expression persisted for more than 1 year without immune rejection or promoter shutoff. Furthermore, when an AAV2 vector carrying human δ-sarcoglycan gene was similarly delivered into the heart of Bio14.6 Syrian hamster, a congestive heart failure and limb girdle muscular dystrophy animal model, widespread therapeutic gene transfer was achieved in a majority of the cardiomyocytes. Efficient expression of the human δ-sarcoglycan gene in the dystrophic hamster hearts restored the entire sarcoglycan complex that was missing due to the primary deficiency of δ-sarcoglycan. Transgene expression persisted for 4 months (the duration of the study) without immune rejection or promoter shutoff. These results indicate that AAV is a promising vector system for cardiac gene therapy.

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References

  1. Harvey BG et al. Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum Gene Ther 2002; 13: 15–63.

    Article  CAS  PubMed  Google Scholar 

  2. Ikeda Y et al. Restoration of deficient membrane proteins in the cardiomyopathic hamster by in vivo cardiac gene transfer. Circulation 2002; 105: 502–508.

    Article  CAS  PubMed  Google Scholar 

  3. Losordo DW et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998; 98: 2800–2804.

    Article  CAS  PubMed  Google Scholar 

  4. Xie Q et al. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA 2002; 99: 10405–10410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kaplitt MG et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet 1994; 8: 148–154.

    Article  CAS  PubMed  Google Scholar 

  6. Ponnazhagan S et al. Adeno-associated virus 2-mediated gene transfer in vivo: organ-tropism and expression of transduced sequences in mice. Gene 1997; 190: 203–210.

    Article  CAS  PubMed  Google Scholar 

  7. Xiao W et al. Adeno-associated virus as a vector for liver directed gene therapy. J Virol 1998; 72: 10222–10226.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Flotte TR et al. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc Nat Acad Sci USA 1993; 90: 10613–10617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xiao X, Li J, Samulski RJ . Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol 1996; 70: 8098–8108.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kessler PD et al. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc Nat Acad Sci USA 1996; 93: 14082–14087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ali RR et al. Gene transfer into the mouse retina mediated by an adeno-associated viral vector. Hum Mol Genet 1996; 5: 591–594.

    Article  CAS  PubMed  Google Scholar 

  12. Flannery JG et al. Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. Proc Nat Acad Sci USA 1997; 94: 6916–6921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cordier L et al. Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer. Mol Ther 2000; 1: 119–129.

    Article  CAS  PubMed  Google Scholar 

  14. Li J et al. rAAV vector-mediated sarcogylcan gene transfer in a hamster model for limb girdle muscular dystrophy. Gene Therapy 1999; 6: 74–82.

    Article  CAS  PubMed  Google Scholar 

  15. Xiao X et al. Full functional rescue of a complete muscle (TA) in dystrophic hamsters by adeno-associated virus vector-directed gene therapy. J Virol 2000; 74: 1436–1442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang B, Li J, Xiao X . Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc Natl Acad Sci USA 2000; 97: 13714–13719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Watchko J et al. Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. Hum Gene Ther 2002; 13: 1451–1460.

    Article  CAS  PubMed  Google Scholar 

  18. Greelish JP et al. Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector. Nat Med 1999; 5: 439–443.

    Article  CAS  PubMed  Google Scholar 

  19. Chao H et al. Persistent expression of canine factor IX in hemophilia B canines. Gene Therapy 1999; 6: 1695–1704.

    Article  CAS  PubMed  Google Scholar 

  20. Kay MA 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  PubMed  Google Scholar 

  21. Song S et al. Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci USA 1998; 95: 14384–14388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fraites Jr TJ et al. Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Mol Ther 2002; 5: 571–578.

    Article  CAS  PubMed  Google Scholar 

  23. Hoffman EP . Counting muscular dystrophies in the post-molecular census. J Neurol Sci 1999; 164: 3–6.

    Article  CAS  PubMed  Google Scholar 

  24. Lim LE, Campbell KP . The sarcoglycan complex in limb-girdle muscular dystrophy. Curr Opin Neurol 1998; 11: 443–452.

    Article  CAS  PubMed  Google Scholar 

  25. Crosbie RH et al. Sarcospan, the 25-kDa transmembrane component of the dystrophin–glycoprotein complex. J Biol Chem 1997; 272: 31221–31224.

    Article  CAS  PubMed  Google Scholar 

  26. Homburger F, Baker JR, Nixon CW, Whitney R . Primary, generalized polymyopathy and cardiac necrosis in an inbred line of Syrian hamsters. Med Exp 1962; 6: 339–345.

    Google Scholar 

  27. Nigro V et al. Identification of the Syrian hamster cardiomyopathy gene. Hum Mol Genet 1997; 6: 601–607.

    Article  CAS  PubMed  Google Scholar 

  28. Sakamoto A et al. Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin-associated glycoprotein complex. Proc Nat Acad Sci USA 1997; 94: 13873–13878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Holt KH et al. Functional rescue of the sarcoglycan complex in the BIO 14.6 hamster using delta-sarcoglycan gene transfer. Mol Cell 1998; 1: 841–848.

    Article  CAS  PubMed  Google Scholar 

  30. Kawada T 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  PubMed  PubMed Central  Google Scholar 

  31. Ono K, Lindsey ES . Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg 1969; 57: 225–229.

    CAS  PubMed  Google Scholar 

  32. Pruchnic R et al. The use of adeno-associated virus to circumvent the maturation-dependent viral transduction of muscle fibers. Hum Gene Ther 2000; 11: 521–536.

    Article  CAS  PubMed  Google Scholar 

  33. Huard J et al. The basal lamina is a physical barrier to herpes simplex virus-mediated gene delivery to mature muscle fibers. J Virol 1996; 70: 8117–8123.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kaplitt MG 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 

  35. Hoshijima M 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  PubMed  Google Scholar 

  36. Asfour B et al. Uniform long-term gene expression using adeno-associated virus (AAV) by ex vivo recirculation in rat-cardiac isografts. Thorac Cardiovasc Surg 2002; 50: 347–350.

    Article  CAS  PubMed  Google Scholar 

  37. Asfour B et al. A simple new model of physiologically working heterotopic rat heart transplantation provides hemodynamic performance equivalent to that of an orthotopic heart. J Heart Lung Transplant 1999; 18: 927–936.

    Article  CAS  PubMed  Google Scholar 

  38. 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 

  39. Summerford C, Bartlett JS, Samulski RJ . AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat Med 1999; 5: 78–82.

    Article  CAS  PubMed  Google Scholar 

  40. Qing K et al. Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat Med 1999; 5: 71–77.

    Article  CAS  PubMed  Google Scholar 

  41. Coral-Vazquez R et al. Disruption of the sarcoglycan–sarcospan complex in vascular smooth muscle: a novel mechanism for cardiomyopathy and muscular dystrophy. Cell 1999; 98: 465–474.

    Article  CAS  PubMed  Google Scholar 

  42. Cohn RD et al. Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan–sarcospan complex. J Clin Invest 2001; 107: R1–R7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xiao X, Li J, Samulski RJ . Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol 1998; 72: 2224–2232.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Snyder R, Xiao X, Samulski RJ . Production of recombinant adeno-associated viral vectors. In: Dracopoli N et al (eds). Current Protocols in Human Genetics. John Wiley & Sons Ltd.: New York, 1996, pp 12.11.11–12.12.23.

    Google Scholar 

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Acknowledgements

We thank Michael Xiao for critical reading of the manuscript. This work is supported by NIH Grants AR 45967 and AR45925 and a grant from Chinese National Science Foundation.

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Authors and Affiliations

  1. Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA

    J Li, T Zhu & X Xiao

  2. Tongji Hospital, Huazhong Science and Technology University, Wuhan, China

    D Wang & T Zhu

  3. Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA

    S Qian & Z Chen

  4. Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    X Xiao

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Li, J., Wang, D., Qian, S. et al. Efficient and long-term intracardiac gene transfer in δ-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectors. Gene Ther 10, 1807–1813 (2003). https://doi.org/10.1038/sj.gt.3302078

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