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.

  • Brief Communication
  • Published:

Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control

Gene Therapy volume 11, pages 1296–1300 (2004)Cite this article

Abstract

Adenovirus (Ad)-mediated gene delivery is a promising approach for genetic manipulation of the vasculature and is being used in both preclinical models and clinical trials. However, safety concerns relating to infection of nontarget tissue and the poor infectivity of vascular cells compared to other cell types necessitates Ad vector refinement. Here, we combine a transductional targeting approach to improve vascular cell infectivity through RGD peptide insertion into adenovirus fibers, combined with transcriptional targeting to endothelial cells using a ≈1 kb fragment of the fms-like tyrosine kinase receptor-1 (FLT-1) promoter. Single- and double-modified vectors were characterized in human cell lines that either support or have silenced FLT-1 expression. In rat hepatocytes and endothelial cells, the double modification substantially shifted transduction profiles toward vascular endothelial cells. Furthermore, in intact aortae derived from spontaneously hypertensive rats that display enhanced αv integrin expression on dysfunctional endothelium, enhanced levels of transduction were observed using the double-modified vector but not in aortae derived from normotensive control rats. Our data indicate that Ad-mediated transduction can be beneficially modified in vitro and in vivo by combining fiber modification and a cell-selective promoter within a single-component vector system.

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Havenga MJE et al. Improved adenovirus vectors for infection of cardiovascular tissues. J Virol 2001; 75: 3335–3342.

    Article  CAS  Google Scholar 

  2. Havenga M et al. Exploiting the natural diversity in adenovirus tropism for therapy and prevention of disease. Virology 2002; 76: 4612–4620.

    Article  CAS  Google Scholar 

  3. Reynolds PN et al. A targetable, injectable adenoviral vector for selective gene delivery to pulmonary endothelium in vivo. Mol Ther 2000; 2: 562–578.

    Article  CAS  Google Scholar 

  4. Bartlett JS, Kleinschmidt J, Boucher RC, Samulski RJ . Targeted adeno-associated virus vector transduction of non-permissive cells mediated by a bi-specific F(ab'gamma)(2) antibody. Nat Biotech 1999; 17: 181–186.

    Article  CAS  Google Scholar 

  5. Nicklin S, Baker A . Tropism-modified adenovirus and adeno-associated viral vectors for gene therapy. Curr Gene Ther 2002; 2: 273–293.

    Article  CAS  Google Scholar 

  6. Dmitriev I et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol 1998; 72: 9706–9713.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Reynolds PN, Dmitriev I, Curiel DT . Insertion of an RGD motif into the HI loop of adenovirus fiber protein alters the distribution of transgene expression of the systemically administered vector. Gene Therapy 1999; 6: 1336–1339.

    Article  CAS  Google Scholar 

  8. Shi W, Bartlett JS . RGD inclusion in VP3 provides adeno-associated virus type 2 (AAV2)-based vectors with a heparan sulfate-independent cell entry mechanism. Mol Ther 2003; 7: 515–525.

    Article  CAS  Google Scholar 

  9. Pasqualini R, Koivunen E, Ruoslahti E . A peptide isolated from phage display libraries is a structural and functional mimic of an RGD-binding site on integrins. J Cell Biol 1995; 130: 1189–1196.

    Article  CAS  Google Scholar 

  10. Bergelson JM et al. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 1997; 275: 1320–1323.

    Article  CAS  Google Scholar 

  11. Tomko RP, Xu R, Philipson L . HCAR and MCAR: The human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc Natl Acad Sci USA 1997; 94: 3352–3356.

    Article  CAS  Google Scholar 

  12. 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 

  13. Hiltunen MO et al. Biodistribution of adenoviral vector to nontarget tissues after local in vivo gene transfer to arterial wall using intravascular and periadventitial gene delivery methods. FASEB J 2000; 14: 2230–2236.

    Article  CAS  Google Scholar 

  14. Nagi P et al. Development of a therapuetic adenoviral vector for cholangiocarcinoma combining tumor-restricted gene expression and infectivity enhancement. J Gastrointest Surg 2003; 7: 364–371.

    Article  Google Scholar 

  15. Nicklin SA et al. Analysis of cell-specific promoters for viral gene therapy targeted at the vascular endothelium. Hypertension 2001; 38: 65–70.

    Article  CAS  Google Scholar 

  16. Reynolds P et al. Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo. Nat Biotechnol 2001; 19: 833–842.

    Article  Google Scholar 

  17. Bauerschmitz G et al. The flt-1 promoter for transcriptional targeting in teratocarcinoma. Cancer Res 2002; 62: 1271–1274.

    CAS  PubMed  Google Scholar 

  18. Nicklin SA et al. Transductional and transcriptional targeting of cancer cells using genetically-engineered viral vectors. Cancer Lett 2003; 201: 165–173.

    Article  CAS  Google Scholar 

  19. Kerr S et al. Superoxide anion production is increased in a model of genetic hypertension: The role of endothelial nitric oxide synthase and superoxide dismutase isoforms. Hypertension 1999; 33: 1353–1358.

    Article  CAS  Google Scholar 

  20. Jeffs B et al. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet 1997; 16: 364–367.

    Article  CAS  Google Scholar 

  21. Dominiczak A et al. Left ventricular hypertophy and arterial blood pressure in experimental models of hypertension. Adv Exp Med Biol 1997; 432: 23–33.

    Article  CAS  Google Scholar 

  22. Fennell JP et al. Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension. Gene Therapy 2002; 9: 110–117.

    Article  CAS  Google Scholar 

  23. Asahara T et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation 1995; 91: 2793–2801.

    Article  CAS  Google Scholar 

  24. Wen S et al. Second-generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall. Arterioscl Thromb Vasc Biol 2000; 20: 1452–1458.

    Article  CAS  Google Scholar 

  25. Intengan HD, Thibault G, Li J-S, Schiffrin EL . Resistance artery mechanics, structure, and extracellular components in spontaneously hypertensive rats: Effects of angiotensin receptor antagonism and converting enzyme inhibition. Circulation 1999; 100: 2267–2275.

    Article  CAS  Google Scholar 

  26. Nicklin SA, Baker AH . Simple methods for preparing recombinant adenoviruses for high efficiency transduction of vascular cells. In: Baker AH (ed) Vascular Disease: Molecular Biology and Gene Transfer Protocols (Methods in Molecular Medicine). Humana Press: New York, 1999.

    Google Scholar 

  27. Nicklin SA et al. Ablating adenovirus type 5 fiber-CAR binding and HI loop insertion of the SIGYPLP peptide generate an endothelial cell-selective adenovirus. Mol Ther 2001; 4: 534–542.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Margaret Cunningham and Nicola Britton for technical assistance and the Biotechnology and Biological Sciences Research Council (17GTH12582 and E17190 to AHB) and British Heart Foundation (PG03/031 to AHB) for financial support.

Author information

Authors and Affiliations

  1. Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    L M Work, N Ritchie, S A Nicklin & A H Baker

  2. University of Adelaide, SA, Australia

    P N Reynolds

Authors
  1. L M Work
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Ritchie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S A Nicklin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P N Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A H Baker
    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

Work, L., Ritchie, N., Nicklin, S. et al. Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control. Gene Ther 11, 1296–1300 (2004). https://doi.org/10.1038/sj.gt.3302292

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302292

Keywords

This article is cited by

Search

Advanced search

Quick links