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