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:

Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice

Abstract

Gene therapy strategies designed to combat haemophilia B, caused by defects in clotting factor IX, have so far concentrated on ex vivo approaches. We have now evaluated adenoviral vector–mediated expression of human factor IX in vivo. Injection of the vector Av1H9B, which encodes human factor IX cDNA, into the tail veins of mice resulted in efficient liver transduction and plasma levels of human factor IX that would be therapeutic for haemophilia B patients. However, levels slowly declined to baseline by nine weeks and were not re–established by a second vector injection. These results address both the advantages and obstacles to the use of adenoviral vectors for treatment of haemophilia B.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Thompson, A.R. Stucture, function, and molecular defects of factor IX. Blood 67, 565–572 (1986).

    CAS  PubMed  Google Scholar 

  2. Prevention and control of haemophilia: Memorandum from a joint WHO/WFA meeting. Bull. World Health Org. 69, 17–26 (1991).

  3. Briet, E. Factor IX inhibitors in haemophilia B patients: their incidence and prospects for development with high purity factor IX products. Blood Coag. Fibrin. 2, (suppl 1) 47–50 (1991).

    Article  Google Scholar 

  4. Hedner, U. & Davie, E.W. Introduction to hemostasis and the vitamin K dependent coagulation factors in The Metabolic Basis of Inherited Diseases Vol. 2, 6 edn (eds Scriver, C. R. et al.) 2116–2134 (McGraw-Hill, New York, N.Y. 1989).

    Google Scholar 

  5. Palmer, T.D., Thompson, A.R. & Miller, A.D. Production of Human factor IX in animals by genetically modified skin fibroblasts: potential therapy for hemophilia B. Blood 73, 438–445 (1989).

    CAS  Google Scholar 

  6. Scharfmann, R., Axelrod, J.H. & Verma, I.M. Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. Proc. natn. Acad. Sci. U.S.A. 88, 4626–4630 (1991).

    Article  CAS  Google Scholar 

  7. Yao, S.N., Wilson, J.M., Nabel, E.G., Kurachi, S., Hachiya, H.L. & Kurachi, K. Expression of human factor IX in rat capillary endothelial cells: toward somatic gene therapy for hemophilia B. Proc. natn. Acad. Sci. U.S.A. 88, 8101–8105 (1991).

    Article  CAS  Google Scholar 

  8. Gerrard, A.J., Hudson, D.L., Brownlee, G.G. & Watt, F.M. Towards gene therapy for haemophilia B using primary human keratinocytes. Nature Genet. 3, 180–183 (1993).

    Article  CAS  Google Scholar 

  9. Dai, Y., Roman, M., Naviaux, R.K. & Verma, I.M. Gene therapy in primary myoblasts: long-term expression of factor IX protein following transplantationin vivo. Proc. natn. Acad. Sci. U.S.A. 89, 10892–10895 (1992).

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  11. Rosenfeld, M.A. et al. Adenovirus-mediated transfer of a recombinant α1-antitrypsin gene to the lung epithelium in vivo.. Science 252, 431–434 (1991).

    Article  CAS  Google Scholar 

  12. 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 

  13. Stratford-Perricaudet, L.D., Makeh, I., Perricaudet, M. & Briand, P. Widespread long-term gene transfer to mouse skeletal muscles and heart. J. clin. Invest. 90, 626–630 (1992).

    Article  CAS  Google Scholar 

  14. Mastrangeli, A. et al. Diversity of airway epithelial cell targets for in vivo recombinant adenovirus-mediated gene transfer. J. cin. Invest. 91, 225–234 (1993).

    Article  CAS  Google Scholar 

  15. Davidson, B.L., Alien, F.D., Kozarsky, K.F., Wilson, J.M. & Roessler, B.J. A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nature Genet. 3, 219–223 (1993).

    Article  CAS  Google Scholar 

  16. Akli, S. et al. Transfer of a foreign gene into the brain using adenovirus vectors. Nature Genet. 3, 224–228 (1993).

    Article  CAS  Google Scholar 

  17. Bajocchi, G., Feldman, S.H., Crystal, R.G. & Mastrangeli, A. Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors. Nature Genet. 3, 229–234 (1993).

    Article  CAS  Google Scholar 

  18. Ragot, T. et al. Efficient adenovirus-mediated transfer of a human minidystrophin gene to skeletal muscle of mdx mice. Nature 361, 647–650 (1993).

    Article  CAS  Google Scholar 

  19. Stratford-Perricaudet, L.D., Levrero, M., Chasse, J., Perricaudet, M. & Briand, P. Evaluation of the transfer and expression in mice of an enzyme-encoding gene using a human adenovirus vector. Hum. gene Ther. 1, 241–256 (1990).

    Article  CAS  Google Scholar 

  20. Jaffe, H.A. et al. Adenovirus-mediated in vivo gene transfer and expression in normal rat liver. Nature Genet. 1, 372–378 (1992).

    Article  CAS  Google Scholar 

  21. Li, Q., Kay, M.A., Finegold, M., Stratford-Perricaudet, L.D. & Woo, S.L.C. Assessment of recombinant adenoviral vectors for hepatic gene therapy. Hum. gene Ther. 4, 403–409 (1993).

    Article  CAS  Google Scholar 

  22. Herz, J. & Gerard, R.D. Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc. natn. Acad. Sci. U.S.A. 90, 2812–2816 (1993).

    Article  CAS  Google Scholar 

  23. Human gene marker/therapy clinical protocols. Hum. gene Ther. 4, 391–398 (1993).

  24. Evans, J.P., Watzke, H.H., Ware, J.L., Stafford, D.W. & High, K.A. Molecular cloning of a cDNA encoding canine factor IX. Blood 74, 207–212 (1989).

    CAS  PubMed  Google Scholar 

  25. Thompson, A.R., Palmer, T.D., Lynch, C.M. & Miller, A.D. Gene transfer as an approach to cure patients with hemophilia A or B. in Biotechnology of Plasma Proteins. Curr. Stud. Hematol. Blood Transf. (eds Albertini, A. et al.) 58, 59–62 (Karger, Basel, 1991).

    Google Scholar 

  26. Thompson, A.R., Forrey, A.W., Gentry, P.A., Smith, K.J. & Harker, L.A. Human factor IX in animals: kinetics from isolated radiolabeled protein and platelet destruction following crude concentrate infusions. Br. J. Haematol. 45, 329–342 (1980).

    Article  CAS  Google Scholar 

  27. Smith, K.J. & Thompson, A.R. Labeled factor IX kinetics in patients with hemophilia B. Blood 58, 625–629 (1981).

    CAS  PubMed  Google Scholar 

  28. Jallat, S. et al. Characterization of recombinant human factor IX expressed in transgenic mice and in derived transimmortalized hepatic cell lines. EMBO J. 9, 3295–3301 (1990).

    Article  CAS  Google Scholar 

  29. DiPersio, C.M., Jackson, D.A. & Zaret, K.S. The extracellular matrix coordinately modulates liver transcription factors and hepatocyte morphology. Molec. cell. Biol. 11, 4405–4414 (1991).

    Article  CAS  Google Scholar 

  30. Horwitz, M.S. Adenoviruses in Fields Virology Vol. 2, 2 edn (eds Fields, B.N. & Knipe, D.M.) 1723–1742 (Raven Press, New York, 1990).

    Google Scholar 

  31. Strober, S. Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships. A. Rev. Immunol. 2, 219–237 (1984).

    Article  CAS  Google Scholar 

  32. Mittal, S.K., McDermott, M.R., Johnson, D.C., Prevec, L. & Graham, F.L. Monitoring foreign gene expression by a human adenovirus-based vector using the firefly luciferase gene as a reporter. Virus Res. 28, 67–90 (1993).

    Article  CAS  Google Scholar 

  33. Shenk, T. & Williams, J. Genetic analysis of adenoviruses. Curr. Top. microbiol. Immunol. 111, 1–39 (1984).

    CAS  PubMed  Google Scholar 

  34. Graham, F.L., Smiley, J., Russell, W.C. & Nairn, R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J. gen. Virol. 36, 59–72 (1977).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smith, T., Mehaffey, M., Kayda, D. et al. Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice. Nat Genet 5, 397–402 (1993). https://doi.org/10.1038/ng1293-397

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1293-397

This article is cited by

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