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  • Original Article
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Readministration of helper-dependent adenovirus to mouse lung

Gene Therapy volume 13, pages 773–780 (2006)Cite this article

Abstract

Adenovirus vectors (Ad) are widely used in gene therapy studies, including those aimed at treating cystic fibrosis lung disease. Various approaches have been investigated to blunt the host immune response to Ad, including development of helper-dependent (HD) Ad. The host cytotoxic T-cell response to HD-Ad is generally lower than to earlier-generation Ad. However, antibodies are formed which could inhibit the efficacy of HD-Ad readministration. In this first study of HD-Ad readministration to the lung, we found that a second administration of HD-Ad to mice was possible with minimal loss of transgene expression. In contrast, when first-generation (FG) Ad was administered initially, followed by HD-Ad or FG-Ad, transgene expression was reduced. Significantly lower concentrations of antibodies against Ad were found in lung lavage fluid and serum from mice that received two doses of HD-Ad (when the initial HD-Ad lacked a transgene), compared to mice that received FG-Ad followed by HD-Ad. These data suggest that readministration of HD-Ad for lung gene therapy may be feasible.

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References

  1. Boucher RC . An overview of the pathogenesis of cystic fibrosis lung disease. Adv Drug Deliv Rev 2002; 54: 1359–1371.

    Article  CAS  PubMed  Google Scholar 

  2. Koehler DR, Hitt MM, Hu J . Challenges and strategies for cystic fibrosis lung gene therapy. Mol Ther 2001; 4: 84–91.

    Article  CAS  PubMed  Google Scholar 

  3. Ayers MM, Jeffery PK . Proliferation and differentiation in mammalian airway epithelium. Eur Respir J 1988; 1: 58–80.

    CAS  PubMed  Google Scholar 

  4. Jooss K, Chirmule N . Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy. Gene Therapy 2003; 10: 955–963.

    Article  CAS  PubMed  Google Scholar 

  5. Parks RJ, Chen L, Anton M, Sankar U, Rudnicki MA, Graham FL . A helper-dependent adenovirus vector system: removal of helper virus by Cre-mediated excision of the viral packaging signal. Proc Natl Acad Sci USA 1996; 93: 13565–13570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Muruve DA, Cotter MJ, Zaiss AK, White LR, Liu Q, Chan T et al. Helper-dependent adenovirus vectors elicit intact innate but attenuated adaptive host immune responses in vivo. J Virol 2004; 78: 5966–5972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Maione D, Wiznerowicz M, Delmastro P, Cortese R, Ciliberto G, La Monica N et al. Prolonged expression and effective readministration of erythropoietin delivered with a fully deleted adenoviral vector. Hum Gene Ther 2000; 11: 859–868.

    Article  CAS  PubMed  Google Scholar 

  8. Brunetti-Pierri N, Palmer DJ, Beaudet AL, Carey KD, Finegold M, Ng P . Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum Gene Ther 2004; 15: 35–46.

    Article  CAS  PubMed  Google Scholar 

  9. Stilwell JL, Samulski RJ . Role of viral vectors and virion shells in cellular gene expression. Mol Ther 2004; 9: 337–346.

    Article  CAS  PubMed  Google Scholar 

  10. Parks R, Evelegh C, Graham F . Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration. Gene Therapy 1999; 6: 1565–1573.

    Article  CAS  PubMed  Google Scholar 

  11. Maione D, Della Rocca C, Giannetti P, D’Arrigo R, Liberatoscioli L, Franlin LL et al. An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus. Proc Natl Acad Sci USA 2001; 98: 5986–5991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chirmule N, Hughes JV, Gao GP, Raper SE, Wilson JM . Role of E4 in eliciting CD4 T-cell and B-cell responses to adenovirus vectors delivered to murine and nonhuman primate lungs. J Virol 1998; 72: 6138–6145.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Varnavski AN, Calcedo R, Bove M, Gao G, Wilson JM . Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naive and pre-immunized mice. Gene Therapy 2005; 12: 427–436.

    Article  CAS  PubMed  Google Scholar 

  14. Harui A, Roth MD, Kiertscher SM, Mitani K, Basak SK . Vaccination with helper-dependent adenovirus enhances the generation of transgene-specific CTL. Gene Therapy 2004; 11: 1617–1626.

    Article  CAS  PubMed  Google Scholar 

  15. Yang Y, Jooss KU, Su Q, Ertl HC, Wilson JM . Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Therapy 1996; 3: 137–144.

    PubMed  Google Scholar 

  16. Michou AI, Santoro L, Christ M, Julliard V, Pavirani A, Mehtali M . Adenovirus-mediated gene transfer: influence of transgene, mouse strain and type of immune response on persistence of transgene expression. Gene Therapy 1997; 4: 473–482.

    Article  CAS  PubMed  Google Scholar 

  17. Chirmule N, Raper SE, Burkly L, Thomas D, Tazelaar J, Hughes JV et al. Readministration of adenovirus vector in nonhuman primate lungs by blockade of CD40-CD40 ligand interactions. J Virol 2000; 74: 3345–3352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Limberis M, Anson DS, Fuller M, Parsons DW . Recovery of airway cystic fibrosis transmembrane conductance regulator function in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer. Hum Gene Ther 2002; 13: 1961–1970.

    Article  CAS  PubMed  Google Scholar 

  19. Koehler DR, Frndova H, Leung K, Louca E, Palmer D, Ng P et al. Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter. J Gene Med 2005; 7: 1409–1420.

    Article  CAS  PubMed  Google Scholar 

  20. Yang Y, Li Q, Ertl HC, Wilson JM . Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol 1995; 69: 2004–2015.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang Y, Su Q, Wilson JM . Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs. J Virol 1996; 70: 7209–7212.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Jooss K, Yang Y, Wilson JM . Cyclophosphamide diminishes inflammation and prolongs transgene expression following delivery of adenoviral vectors to mouse liver and lung. Hum Gene Ther 1996; 7: 1555–1566.

    Article  CAS  PubMed  Google Scholar 

  24. Morral N, O’Neal W, Zhou H, Langston C, Beaudet A . Immune responses to reporter proteins and high viral dose limit duration of expression with adenoviral vectors: comparison of E2a wild type and E2a deleted vectors. Hum Gene Ther 1997; 8: 1275–1286.

    Article  CAS  PubMed  Google Scholar 

  25. Jooss K, Turka LA, Wilson JM . Blunting of immune responses to adenoviral vectors in mouse liver and lung with CTLA4Ig. Gene Therapy 1998; 5: 309–319.

    Article  CAS  PubMed  Google Scholar 

  26. O’Neal WK, Rose E, Zhou H, Langston C, Rice K, Carey D et al. Multiple advantages of alpha-fetoprotein as a marker for in vivo gene transfer. Mol Ther 2000; 2: 640–648.

    Article  PubMed  Google Scholar 

  27. Croyle MA, Chirmule N, Zhang Y, Wilson JM . ‘Stealth’ adenoviruses blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung. J Virol 2001; 75: 4792–4801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kaplan JM, Armentano D, Sparer TE, Wynn SG, Peterson PA, Wadsworth SC et al. Characterization of factors involved in modulating persistence of transgene expression from recombinant adenovirus in the mouse lung. Hum Gene Ther 1997; 8: 45–56.

    Article  CAS  PubMed  Google Scholar 

  29. Kerem B, Kerem E . The molecular basis for disease variability in cystic fibrosis. Eur J Hum Genet 1996; 4: 65–73.

    Article  CAS  PubMed  Google Scholar 

  30. Dorin JR, Farley R, Webb S, Smith SN, Farini E, Delaney SJ et al. A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction. Gene Therapy 1996; 3: 797–801.

    CAS  PubMed  Google Scholar 

  31. Kaplan JM, St George JA, Pennington SE, Keyes LD, Johnson RP, Wadsworth SC et al. Humoral and cellular immune responses of nonhuman primates to long-term repeated lung exposure to Ad2/CFTR-2. Gene Therapy 1996; 3: 117–127.

    CAS  PubMed  Google Scholar 

  32. Zabner J, Petersen DM, Puga AP, Graham SM, Couture LA, Keyes LD et al. Safety and efficacy of repetitive adenovirus-mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats. Nat Genet 1994; 6: 75–83.

    Article  CAS  PubMed  Google Scholar 

  33. Wilson CB, Embree LJ, Schowalter D, Albert R, Aruffo A, Hollenbaugh D et al. Transient inhibition of CD28 and CD40 ligand interactions prolongs adenovirus-mediated transgene expression in the lung and facilitates expression after secondary vector administration. J Virol 1998; 72: 7542–7550.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Crystal RG, McElvaney NG, Rosenfeld MA, Chu CS, Mastrangeli A, Hay JG et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet 1994; 8: 42–51.

    Article  CAS  PubMed  Google Scholar 

  35. Bellon G, Michel-Calemard L, Thouvenot D, Jagneaux V, Poitevin F, Malcus C et al. Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial. Hum Gene Ther 1997; 8: 15–25.

    Article  CAS  PubMed  Google Scholar 

  36. Harvey BG, Hackett NR, Ely S, Crystal RG . Host responses and persistence of vector genome following intrabronchial administration of an E1(−)E3(−) adenovirus gene transfer vector to normal individuals. Mol Ther 2001; 3: 206–215.

    Article  CAS  PubMed  Google Scholar 

  37. Harvey BG, Hackett NR, El-Sawy T, Rosengart TK, Hirschowitz EA, Lieberman MD et al. Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs. J Virol 1999; 73: 6729–6742.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Harvey BG, Maroni J, O’Donoghue KA, Chu KW, Muscat JC, Pippo AL 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 

  39. Ahmed R, Gray D . Immunological memory and protective immunity: understanding their relation. Science 1996; 272: 54–60.

    Article  CAS  PubMed  Google Scholar 

  40. Koehler DR, Sajjan U, Chow Y-H, Martin B, Kent G, Tanswell AK et al. Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia. Proc Natl Acad Sci USA 2003; 100: 15364–15369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Toietta G, Koehler DR, Finegold M, Lee B, Hu J, Beaudet AL . Reduced inflammation and improved airway expression using helper-dependent adenoviral vectors with a K18 promoter. Mol Ther 2003; 7: 649–658.

    Article  CAS  PubMed  Google Scholar 

  42. Morral N, O’Neal W, Rice K, Leland M, Kaplan J, Piedra PA et al. Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proc Natl Acad Sci USA 1999; 96: 12816–12821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim IH, Jozkowicz A, Piedra PA, Oka K, Chan L . Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci USA 2001; 98: 13282–13287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chirmule N, Propert K, Magosin S, Qian Y, Qian R, Wilson J . Immune responses to adenovirus and adeno-associated virus in humans. Gene Therapy 1999; 6: 1574–1583.

    Article  CAS  PubMed  Google Scholar 

  45. Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D et al. Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States. Clin Diagn Lab Immunol 2004; 11: 351–357.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang Y, Trinchieri G, Wilson JM . Recombinant IL-12 prevents formation of blocking IgA antibodies to recombinant adenovirus and allows repeated gene therapy to mouse lung. Nat Med 1995; 1: 890–893.

    Article  CAS  PubMed  Google Scholar 

  47. Kay MA, Meuse L, Gown AM, Linsley P, Hollenbaugh D, Aruffo A et al. Transient immunomodulation with anti-CD40 ligand antibody and CTLA4Ig enhances persistence and secondary adenovirus-mediated gene transfer into mouse liver. Proc Natl Acad Sci USA 1997; 94: 4686–4691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sandig V, Youil R, Bett AJ, Franlin LL, Oshima M, Maione D et al. Optimization of the helper-dependent adenovirus system for production and potency in vivo. Proc Natl Acad Sci USA 2000; 97: 1002–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Graham FL, Smiley J, Russell WC, Nairn R . Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol 1977; 36: 59–74.

    Article  CAS  PubMed  Google Scholar 

  50. Palmer D, Ng P . Improved system for helper-dependent adenoviral vector production. Mol Ther 2003; 8: 846–852.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We to thank Airi Harui (UCLA School of Medicine, Los Angeles, CA, USA) and Rongqi Duan (Hospital for Sick Children, Toronto, Canada) for technical help, and Merck & Co. (USA) for providing pC4HSU and H14 virus. This work was supported by Operating Grants from the Canadian Institutes of Health Research and from the Canadian Cystic Fibrosis Foundation to JH. JH is a CCFF Scholar and holds a Premier's Research Excellence Award of Ontario. PN holds NIH Grant P50 HL59314.

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Author notes

  1. D R Koehler

    Present address: Drug Royalty Corporation, Royal Bank Plaza, Suite 3120 South Tower, 200 Bay, St., Toronto, Ontario, Canada, M5J 2J3

Authors and Affiliations

  1. Programmes in Lung Biology Research, The Hospital for Sick Children, Toronto, Canada

    D R Koehler, B Martin, A K Tanswell & J Hu

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

    D R Koehler, M Corey & J Hu

  3. Programmes in Population Health Sciences, The Hospital for Sick Children, Toronto, Canada

    M Corey

  4. Department of Paediatrics, University of Toronto, Toronto, Canada

    M Corey, A K Tanswell & J Hu

  5. Department of Public Health Sciences, University of Toronto, Toronto, Canada

    D Palmer

  6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    D Palmer & P Ng

  7. Department of Physiology, University of Toronto, Toronto, Canada

    A K Tanswell

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Correspondence to J Hu.

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Supplementary Information accompanies the paper on the Gene Therapy website (http://www.nature.com/gt).

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Koehler, D., Martin, B., Corey, M. et al. Readministration of helper-dependent adenovirus to mouse lung. Gene Ther 13, 773–780 (2006). https://doi.org/10.1038/sj.gt.3302712

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