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.

  • Research Article
  • Published:

A tropism-modified adenoviral vector increased the effectiveness of gene therapy for arthritis

Gene Therapy volume 8, pages 1785–1793 (2001)Cite this article

Abstract

Adenoviral vectors (AdV) are used for anti-inflammatory cytokine therapy in experimental arthritis. Cell entry of AdV is dependent on the initial recognition of the coxsackie-adenovirus receptor (CAR) on cells. Recently, an Arg-Gly-Asp (RGD) motif was introduced in the HI loop of the fiber knob, this enables the adenovirus to bypass CAR and mediate cell entry via RGD binding integrins. In this study, we explored the transduction efficiency of the RGD-modified adenovirus in synovium and compared the RGD-modified with the conventional adenoviral vector for their effectiveness to modulate the murine collagen-induced arthritis (CIA) model when used to overexpress mIL-1Ra in the knee joint. Twenty-four hours after intra-articular injection of 107 fluorescent forming units (ffu) virus, luciferase (luc) activity in Ad5LucRGD-injected joints was up to 38 times higher than in AdCMVLuc-injected joints, and in arthritic joints the transduction efficiency was up to 69 times higher for the Ad5LucRGD viruses. Transduction of the synovial lining by the RGD-modified adenovirus containing the mIL-1Ra transgene, markedly improved the inhibition of CIA compared with the conventional virus in both a prophylactic and therapeutic treatment protocol. These results show that targeting integrins with the RGD-modified AdV improved the outcome of gene therapy for arthritis.

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
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Evans CH et al. Gene therapy for rheumatic diseases Arthritis Rheum 1999 42: 1–16

    Article  CAS  PubMed  Google Scholar 

  2. Pap T, Gay RE, Gay S . Gene transfer: from concept to therapy Curr Opin Rheumatol 2000 12: 205–210

    Article  CAS  PubMed  Google Scholar 

  3. Wickham TJ, Mathias P, Cheresh DA, Nemerow GR . Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment Cell 1993 73: 309–319

    Article  CAS  PubMed  Google Scholar 

  4. Mathias P, Wickham TJ, Moore M, Nemerow G . Multiple adenovirus serotypes use alpha v integrins for infection J Virol 1994 68: 6811–6814

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bai M, Harfe B, Freimuth P . Mutations that alter an Arg-Gly-Asp (RGD) sequence in the adenovirus type 2 penton base protein abolish its cell-rounding activity and delay virus reproduction in flat cells J Virol 1993 67: 5198–5205

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hidaka C et al. CAR-dependent and CAR-independent pathways of adenovirus vector-mediated gene transfer and expression in human fibroblasts J Clin Invest 1999 103: 579–587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Goossens PH . Infection efficiency of type 5 adenoviral vectors in synovial tissue can be enhanced with a type 16 fiber Arthritis Rheum 2001 44: 570–577

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Demaziere A, Athanasou NA . Adhesion receptors of intimal and subintimal cells of the normal synovial membrane J Pathol 1992 168: 209–215

    Article  CAS  PubMed  Google Scholar 

  10. Rinaldi N et al. Differential expression and functional behaviour of the alpha v and beta 3 integrin subunits in cytokine stimulated fibroblast-like cells derived from synovial tissue of rheumatoid arthritis and osteoarthritis in vitro Ann Rheum Dis 1997 56: 729–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baeten D et al. Comparative study of the synovial histology in rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: influence of disease duration and activity Ann Rheum Dis 2000 59: 945–953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pirila L, Heino J . Altered integrin expression in rheumatoid synovial lining type B cells: in vitro cytokine regulation of alpha 1 beta 1, alpha 6 beta 1, and alpha v beta 5 integrins J Rheumatol 1996 23: 1691–1698

    CAS  PubMed  Google Scholar 

  13. Nikkari L et al. Localization of the alpha v subfamily of integrins and their putative ligands in synovial lining cell layer J Rheumatol 1995 22: 16–23

    CAS  PubMed  Google Scholar 

  14. Joosten LAB, Helsen MM, Van de Loo FAJ, Van den Berg WB . Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. A comparative study using anti-TNF alpha, anti-IL-1 alpha/beta, and IL-1Ra Arthritis Rheum 1996 39: 797–809

    Article  CAS  PubMed  Google Scholar 

  15. Joosten LAB et al. IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation J Immunol 1999 163: 5049–5055

    CAS  PubMed  Google Scholar 

  16. Bakker AC et al. Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human interleukin-1 receptor antagonist protein in the knee Arthritis Rheum 1997 40: 893–900

    Article  CAS  PubMed  Google Scholar 

  17. Joosten LAB et al. Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction Arthritis Rheum 1997 40: 249–260

    Article  CAS  PubMed  Google Scholar 

  18. Ruoslahti E . RGD and other recognition sequences for integrins Annu Rev Cell Dev Biol 1996 12: 697–715

    Article  CAS  PubMed  Google Scholar 

  19. Rinaldi N et al. Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins Ann Rheum Dis 1997 56: 45–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Blackwell JL et al. Using a tropism-modified adenoviral vector to circumvent inhibitory factors in ascites fluid Hum Gene Ther 2000 11: 1657–1669

    Article  CAS  PubMed  Google Scholar 

  21. Rosenberg SA et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens J Natl Cancer Inst 1998 90: 1894–1900

    Article  CAS  PubMed  Google Scholar 

  22. Schulick AH et al. Established immunity precludes adenovirus-mediated gene transfer in rat carotid arteries. Potential for immunosuppression and vector engineering to overcome barriers of immunity J Clin Invest 1997 99: 209–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Joosten LAB, Helsen MM, Van de Loo FAJ, Van den Berg WB . Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. A comparative study using anti-TNF, alpha anti-IL-1 alpha/beta, and IL-1Ra Arthritis Rheum 1996 39: 797–809

    Article  CAS  PubMed  Google Scholar 

  24. Reynolds P, Dmitriev I, Curiel D . 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  PubMed  Google Scholar 

  25. Reynolds P, Dmitriev I, Curiel D . Insertion of an RGD motif into the HI loop of adenovirus fiber protein alters the distribution of transgene expression of the systemically administered vector

  26. Wu P et al. Mutational analysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism J Virol 2000 74: 8635–8647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Girod A et al. Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2 Nat Med 1999 5: 1052–1056

    Article  CAS  PubMed  Google Scholar 

  28. Bartlett JS, Kleinschmidt J, Boucher RC, Samulski RJ . Targeted adeno-associated virus vector transduction of nonpermissive cells mediated by a bispecific F(ab′gamma)2 antibody Nat Biotechnol 1999 17: 181–186

    Article  CAS  PubMed  Google Scholar 

  29. Chartier C et al. Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli J Virol 1996 70: 4805–4810

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mittereder N, March KL, Trapnell BC . Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy J Virol 1996 70: 7498–7509

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Erbacher P . Methods for adenovirus-mediated gene transfer to airway epithelium Robbins PD (eds); Methods in Molecular Medicine, Gene Therapy Protocols Humana Press 1997 169–184

  32. van Meurs JB et al. Quantification of mRNA levels in joint capsule and articular cartilage of the murine knee joint by RT-PCR: kinetics of stromelysin and IL-1 mRNA levels during arthritis Rheumatol Int 1997 16: 197–205

    Article  CAS  PubMed  Google Scholar 

  33. Van Noorden CJ, Vogels IMC . Enzyme histochemical reactions in unfixed and undecalcified cryostat sections of mouse knee joints with special reference to artritic lesions Histochemistry 1986 6: 127–133

    Article  Google Scholar 

  34. van den Broek MF, Van den Berg WB, van de Putte LB, Severijnen AJ . Streptococcal cell wall-induced arthritis and flare-up reaction in mice induced by homologous or heterologous cell walls Am J Pathol 1988 133: 139–149

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Joosten LAB et al. Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction Arthritis Rheum 1997 40: 249–260

    Article  CAS  PubMed  Google Scholar 

  36. Van den Berg WB, van de Putte LB, Zwarts WA, Joosten LAB . Electrical charge of the antigen determines intra-articular antigen handling and chronicity of arthritis in mice J Clin Invest 1984 74: 1850–1859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by the Dutch Rheumatism Association (grant 941), by the Dutch Organization for Scientific Research (project 902-27-218), by the National Institute of Health (R01 CA74242, and R01 CA86881), by the United States Department of Defense (P50 CA89019, and P50 CA83591), and the Juvenile Diabetes Foundation. We thank Dr PLEM van Lent of our laboratory for the human biopsies and the ROG synoviocyte cell-line. We also like to thank the animal care facility for animal care.

Author information

Authors and Affiliations

  1. University Hospital Nijmegen, Nijmegen, The Netherlands

    AC Bakker, FAJ Van de Loo, LAB Joosten, MB Bennink, OJ Arntz & WB van den Berg

  2. Gene Therapy Center at the University of Alabama at Birmingham, Birmingham, AL, USA

    IP Dmitriev, EA Kashentsera & DT Curiel

Authors
  1. AC Bakker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. FAJ Van de Loo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. LAB Joosten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. MB Bennink
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. OJ Arntz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. IP Dmitriev
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. EA Kashentsera
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. DT Curiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. WB van den Berg
    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

Bakker, A., Van de Loo, F., Joosten, L. et al. A tropism-modified adenoviral vector increased the effectiveness of gene therapy for arthritis. Gene Ther 8, 1785–1793 (2001). https://doi.org/10.1038/sj.gt.3301612

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301612

Keywords

This article is cited by

Search

Advanced search

Quick links