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Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types

Abstract

Adenovirus (Ad) is used as a vector for gene delivery in therapies involving genetic disease, vascular disease, and cancer. The first step for efficient gene transfer is effective virus binding to the target cells. We have found that Ad-mediated gene delivery to multiple cell types is much less efficient compared to epithelial-derived cells. Low gene delivery to nonepithelial cell types was directly correlated to a deficiency of the cellular receptor which mediates Ad binding. To overcome this inefficiency we constructed a new virus, AdPK, that contains a heparin-binding domain that targets the virus to broadly expressed, heparan-containing cellular receptors. AdPK delivers genes to multiple cell types at markedly higher efficiencies than unmodified Ad. Viruses with enhanced attachment characteristics significantly improve gene transfer efficiency and may expand the tissues amenable to efficient Ad-mediated gene therapy.

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References

  1. Rosenfeld, M.A., Yoshimura, K., Trapnell, B.C., Yoneyama, K., Rosenthal, E.R., Dalemans, W. et al. 1992. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68: 143–155.

    Article  CAS  PubMed  Google Scholar 

  2. Quantin, B., Perricaudet, L.D., Tajbakhsh, S. and Mandel, J.L. 1992. Adenovirus as an expression vector in muscle cells in vivo. Proc. Natl. Acad. Sci. USA 89: 2581–2584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lemarchand, P., Jaffe, H.A., Danel, C., Cid, M.C., Kleinman, H.K., Stratford-Perricaudet, L.D. et al. 1992. Adenovirus-mediated transfer of a recombinant human α 1-antitrypsin cDNA to human endothelial cells. Proc. Natl. Acad. Sci. USA 89: 6482–6486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Anton, M. and Graham, F.L. 1995. Site-specific recombination mediated by an adenovirus vector expressing the ere recombinase protein: a molecular switch for control of gene expression. J. Virol. 69: 4600–4606.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Le Gal La Salle, G., Robert, J.J., Berrard, S., Ridoux, V., Stratford-Perricaudet, L.D., Perricaudet, M. et al. 1993. An adenovirus vector for gene transfer into neurons and glia in the brain. Science 259: 988–990.

    Article  CAS  PubMed  Google Scholar 

  6. Grubb, B.R., Pickles, R.J., Ye, H., Yankaskas, J.R., Vick, R.N., Engelhardt, J.F. et al. 1994. Inefficient gene transfer by adenovirus vector to cystic fibrosis airway epithelia of mice and humans. Nature 371: 802–806.

    Article  CAS  PubMed  Google Scholar 

  7. Dupuit, F., Zahm, J.-M., Pierrot, D., Brezillon, S., Bonnet, N., Imler, J.-L. et al. 1995. Regenerating cells in human airway surface epithelium represent preferential targets for recombinant adenovirus. Human Gene Therapy 6: 1185–1193.

    Article  CAS  PubMed  Google Scholar 

  8. Acsadi, G., Jani, A., Huard, J., Blaschuk, K., Massie, B., Holland, P. et al. 1994. Cultured human myoblasts and myotubes show markedly different transducibility by replication-defective adenovirus recombinants. Gene Ther. 1: 338–340.

    CAS  PubMed  Google Scholar 

  9. Acsadi, G., Lochmuller, H., Jani, A., Huard, J., Massie, B., Prescott, S. et al. 1996. Dystrophin expression in muscles of mdx mice after adenovirus-mediated in vivo gene transfer. Hum. Gene Ther. 7: 129–140.

    Article  CAS  PubMed  Google Scholar 

  10. March, K.L., Madison, J.E. and Trapnell, B.C. 1995. Pharmocokinetics of adenoviral vector-mediated gene delivery to vascular smooth muscle cells: modulation by poloxamer 407 and implications for cardiovascular gene therapy. Hum. Gene Ther. 6: 41–53.

    Article  CAS  PubMed  Google Scholar 

  11. Heikkila, P., Parpala, T., Lukkarinen, O., Weber, M. and Tryggvason, K. 1996. Adenovirus-mediated gene transfer into kidney glomeruli using an exvivo and in vivo kidney perfusion system—first steps towards gene therapy of Alport syndrome. Gene Ther. 3: 21–27.

    CAS  PubMed  Google Scholar 

  12. Huang, S., Endo, R.I. and Nemerow, G.R. 1995. Upregulation of integrins αvβ3 and αvβ5 on human monocytes and T lymphocytes facilitates adenovirus-mediated gene delivery. J. Virol. 69: 2257–2263.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wattel, E., Vanrumbeke, M., Abina, M.A., Cambier, N., Preudhomme, C., Haddada, H. et al. 1996. Differential efficacy of adenoviral mediated gene transfer into cells from hematological cell lines and fresh hematological malignancies. Leukemia 10: 171–174.

    CAS  PubMed  Google Scholar 

  14. Pickles, R.J., Barker, P.M., Ye, H. and Boucher, R.C. 1996. Efficient adenovirus-mediated gene transfer to basal but not columnar cells of cartilaginous airway epithelia. Hum. Gene Ther. 7: 921–931.

    Article  CAS  PubMed  Google Scholar 

  15. Philipson, L., Lonberg-Holm, K. and Pettersson, U. 1968. Virus-receptor interaction in an adenovirus system. J. Virol. 2: 1064–1075.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wickham, T.J., Mathias, P., Cheresh, D.A. and Nemerow, G.R. 1993. Integrins αv7beta;3 and αvβ5 promote adenovirus internalization but not virus attachment. Cell 73: 309–319.

    Article  CAS  PubMed  Google Scholar 

  17. Defer, C., Belin, M.T., Caillet-Boudin, M.L. and Boulanger, P. 1990. Human adenovirus-host cell interactions: comparative study with members of subgroups B and C. J. Virol. 64: 3661–3673.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Stevenson, S.C., Rollence, M., White, B., Weaver, L. and McClelland, A. 1995. Human adenovirus serotypes 3 and 5 bind to two different cellular receptors via the fiber head domain. J. Virol. 69: 2850–2857.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Mathias, P., Wickham, T., Moore, M. and Nemerow, G. 1994. Multiple adenovirus serotypes use αv integrins for infection. J. Virol. 68: 6811–6814.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Jalkanen, M., Jalkanen, S. and Bernfield, M. 1991. Binding of extracellular effector molecules by cell surface proteoglycans, pp. 1–30 in Receptors for extracellular matrix. McDonald, J.A. and Mecham, R.P. (eds.). Academic Press, New York.

    Google Scholar 

  21. Michael, S.I., Hong, J.S., Curiel, D.T. and Engler, J.A. 1995. Addition of a short peptide ligand to the adenovirus fiber protein. Gene Ther. 2: 660–668.

    CAS  PubMed  Google Scholar 

  22. Wickham, T.J., Carrion, M.E. and Kovesdi, I. 1995. Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs. Gene Ther. 2: 750–756.

    CAS  PubMed  Google Scholar 

  23. Wickham, T.J., Segal, D.M., Roelvink, P.W., Carrion, M.E., Lizonova, A., Lee, G.M. et al. 1996. Targeted adenovirus gene transfer to endothelial and smooth muscle cells by using bispecific antibodies. J. Virol. 70: 6831–6838.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chroboczek, J. and Jacrot, B. 1987. The sequence of adenovirus fiber: similarities and differences between serotypes 2 and 5. Virology 161: 549–554.

    Article  CAS  PubMed  Google Scholar 

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Wickham, T., Roelvink, P., Brough, D. et al. Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types. Nat Biotechnol 14, 1570–1573 (1996). https://doi.org/10.1038/nbt1196-1570

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  • DOI: https://doi.org/10.1038/nbt1196-1570

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