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.

  • Article
  • Published:

Safety and efficacy of repetitive adenovirus–mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats

Nature Genetics volume 6, pages 75–83 (1994)Cite this article

Abstract

Gene therapy for cystic fibrosis (CF) will require the safe transfer of CFTR cDNA to airway epithelia in vivo. We showed previously that a recombinant adenovirus, Ad2/ CFTR–1, expresses CFTR in vitro. As adenovirus rarely integrates, treatment will require repeated vector administration. We applied Ad2/CFTR-1 to intrapulmonary airway epithelia of cotton rats and nasal epithelia of Rhesus monkeys. In both species we detected CFTR mRNA and protein after repeated administration and in monkeys, protein was detected six weeks after repeat administration. The vector did not replicate and was rapidly cleared. Despite an antibody response, there was no evidence of a local or systemic inflammatory response after repeat administration. These data indicate that repetitive administration of Ad2/CFTR-1 is both safe and efficacious.

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

Similar content being viewed by others

References

  1. Boat, T.F., Welsh, M.J. & Beaudet, A.L.,Cystolic Fibrosis. In Metabolic. Basis of Inherited Disease. (eds Scriver, C.R. et al.) 2649–2680 (McGraw-Hill, New York, 1989).

    Google Scholar 

  2. Ouinton, P.M. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 4, 2709–2717 (1990).

    Article  Google Scholar 

  3. Boucher, R.C., Knowles, M.R. Stutts, M.J. & Gatzy, J.T. Epithelial dysfunction In cystic fibrosis lung disease. Lung 161, 1–17 (1983).

    Article  Google Scholar 

  4. Rommens, J.M. et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245, 1059–1065 (1989).

    Article  CAS  Google Scholar 

  5. Riordan, J.R. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066–1073 (1989).

    Article  CAS  Google Scholar 

  6. Kerem, B-S. et al. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073–1080 (1989).

    Article  CAS  Google Scholar 

  7. Welsh, M.J. et al. Cystic fibrosis transmembrane conductance regulator: A chloride channel with novel regulation. Neuron 8, 821–829 (1992).

    Article  CAS  Google Scholar 

  8. Mclntosh, I. & Cutting, G.R. Cystic fibrosis transmembrane conductance regulator and etiology and pathogenesis of cystic fibrosis. FASEB J. 6, 2775–2782 (1992).

    Article  Google Scholar 

  9. Riordan, J.R. The cystic fibrosis transmembrane conductance regulator. Ann. Rev. Phystol. 55, 609–630 (1993).

    Article  CAS  Google Scholar 

  10. Cheng, S.H. et al. Defective intraCellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63, 827–634 (1990).

    Article  CAS  Google Scholar 

  11. Denning, G.M., Ostedgaard, L.S. & Welsh, M.J. Abnormal localization of cystic fibrosis transmembrane conductance regulator in primary cultures of cystic fibrosis airway eplthelia. J. Cell Biol. 18, 551–559 (1992).

    Article  Google Scholar 

  12. Kartner, N., Augustlnas, O., Jensen, T.J., Naismith, A.L. & Riordan, J.R. Mislocalization of δF508 CFTR in cystic fibrosis sweat gland. Nature Genet. 1, 321–327 (1992).

    Article  CAS  Google Scholar 

  13. Rich, D.P. et al. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation In cystic fibrosis airway epithelial cells. Nature 347, 358–363 (1990).

    Article  CAS  Google Scholar 

  14. Drumm, M.L. et al. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell 62,1227–1233 (1990).

    Article  CAS  Google Scholar 

  15. Berkner, K.L. Development of adenovirus vectors for the expression of heterologous genes. Biotechniques 6, 616–629 (1988).

    CAS  Google Scholar 

  16. Graham, F.L. & Prevec, L. Adenovirus-based expression vectors and recombinant vaccines. In Vaccines: New Approaches to Immunological Problems. (ed. Ellis, R. W.) 363–390 (Butterworth-Helnemann, Boston, 1992).

    Chapter  Google Scholar 

  17. Rosenfeld, M.A. et al. Adenovlrus-mediated transfer of a recombinant α1-antitrypsin gene to the lung epithelium In vivo. Science 262, 431–434 (1991).

    Article  Google Scholar 

  18. Rosenfeld, M.A. et al. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68, 143–155 (1992).

    Article  CAS  Google Scholar 

  19. Mastrangeli, A. et al. Diversity of airway epithelial Cell targets for in vivo recombinant adenovirus-medlated gene transfer. J. din. Invest. 91, 225–234 (1993).

    CAS  Google Scholar 

  20. Engelhardt, J.F. et al. Direct gene transfer of human CFTR into human bronchial epithelia of xenografts with EI-deletedadenoviruses. Nature Genet. 4, 27–34 (1993).

    Article  CAS  Google Scholar 

  21. Rich, D.P. et al. Development and analysis of recombinant adenoviruses for gene therapy of cystic fibros. Hum. gene Ther. 4, 461–476 (1993).

    Article  CAS  Google Scholar 

  22. Prince, G.A. et al. Pathogenesis of adenovirus type 5 pneumonia in cotton rats (Sigmodon hispidus). J. Virol. 67, 101–111 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ginsberg, H.S. et al. Role of early region E (E3) in pathogenesis of adenovirus disease. Proc. natn. Acad. Sci. U.S.A. 86, 3823–3827 (1989).

    Article  CAS  Google Scholar 

  24. Harkema, R. et al. Non-olfactory surface epithelium of the nasalcavity of the bonnet monkey: A morphologic and morphometric study of the transitional and respiratory epithelium. Am. J. Anat. 180, 266–279 (1987).

    Article  CAS  Google Scholar 

  25. Knowles, M., Gatzy, J. & Boucher, R. Relative ion permeability of normal and cystic fibrosis nasal epithelium. J. din. Invest. 71, 1410–1417 (1983).

    CAS  Google Scholar 

  26. Yankaskas, J.R., Cotton, C.U., Knowles, M.R., Gatzy, J.T. & Boucher, R.C. Culture of human nasal epithelial cells on collagen matrix supports. A comparison of bioelectric properties of normal and cystic fibrosis epithelia. Am. Rev. respir. Dis. 132, 1281–1287 (1985).

    CAS  PubMed  Google Scholar 

  27. Welsh, M.J. Electrolyte transport by airway epithelia. Physiol. Rev. 67, 1143–1184 (1987).

    Article  CAS  Google Scholar 

  28. Trapnell, B.C. et al. Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis. Proc. nafn. Acad. Sci. U.S.A. 88, 6565–6569 (1991).

    Article  CAS  Google Scholar 

  29. Engelhardt, J.F. & Wilson, J.M. Submucosal glands are the predominant site of CFTR expression inthe human bronchus. Nature Genet 2, 240–248 (1992).

    Article  CAS  Google Scholar 

  30. Johnson, L.G. et al. Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis. Nature Genet. 2, 21–25 (1992).

    Article  CAS  Google Scholar 

  31. Ginsberg, H.S. et al. A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. Proc. natn. Acad. Sci. U.S.A. 88, 1651–1655 (1991).

    Article  CAS  Google Scholar 

  32. Graham, F.L., Smiley, J., Russell, W.L. & Nairn, A.N. Characterization of a human cell line transformed by DNA from adenovirus 5. J. gen. Virol. 36, 59–72 (1977).

    Article  CAS  Google Scholar 

  33. Denning, G.M., Ostedgaard, L.S., Cheng, S.H., Smith, A.E. & Welsh, M.J. Localization of cystic fibrosis transmembrane conductance regulator in chloride secretory epithelia. J. din. Invest. 89, 339–349 (1992).

    CAS  Google Scholar 

  34. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanldinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  35. Hanson, C.A., Holbrook, E.A., Sheldon, S., Schnitzer, B. & Roth, M. Detection of Philadelphia chromosome-positive Cells from glass slide smears using the polymerase chain reaction. Am. J. Pathoi. 137,1–6 (1990).

    CAS  Google Scholar 

  36. Sambrook, J., Fritsch, E.F. & Maniatis, T. in Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, Departments of Internal Medicine, Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa, 52242, USA

    Joseph Zabner, Deanna M. Petersen, Aurita P. Puga & Michael J. Welsh

  2. Otolaryngology, University of Iowa College of Medicine, Iowa City, Iowa, 52242, USA

    Scott M. Graham

  3. Genzyme Corporation, One Mountain Road, Framingham, Massachusetts, 01701, USA

    Larry A. Couture, Lynn D. Keyes, Mike J. Lukason, Judith A. St. George, Richard J. Gregory & Alan E. Smith

Authors
  1. Joseph Zabner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deanna M. Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aurita P. Puga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Scott M. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Larry A. Couture
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lynn D. Keyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mike J. Lukason
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Judith A. St. George
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Richard J. Gregory
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alan E. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael J. Welsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zabner, J., Petersen, D., Puga, A. et al. Safety and efficacy of repetitive adenovirus–mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats. Nat Genet 6, 75–83 (1994). https://doi.org/10.1038/ng0194-75

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0194-75

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing