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CAR- or αv integrin-binding ablated adenovirus vectors, but not fiber-modified vectors containing RGD peptide, do not change the systemic gene transfer properties in mice

Gene Therapy volume 9, pages 769–776 (2002)Cite this article

Abstract

Targeted gene delivery to the tissue of interest by recombinant adenovirus (Ad) vectors is limited by the relatively broad expression of the primary receptor, the coxsackievirus and adenovirus receptor (CAR), and the secondary receptor, αv integrin. This problem could be overcome by mutating the fiber and penton base, which bind with CAR and αv integrin, respectively. In this study, we constructed CAR-binding ablated Ad vectors and αv integrin-binding ablated Ad vectors by mutation in the FG loop of fiber knob and in the RGD motif of penton base, respectively, and compared the gene transfer properties of their vectors into various types of cultured cells and mice with conventional Ad vectors. We also generated Ad vectors containing RGD peptide in the HI loop of the fiber knob. CAR-binding ablated Ad vectors mediated about 1% of gene transfer activity into CAR-positive cultured cells, compared with conventional Ad vectors, while αv integrin-binding ablated Ad vectors maintained at least 76% of gene transfer activity into cultured CAR-positive cells. Inclusion of the RGD peptide into the HI loop of the fiber knob of CAR-binding ablated Ad vectors restored gene transfer activity in vitro. On the other hand, systemically administered CAR-binding ablated Ad vectors, as well as αv integrin-binding ablated Ad vectors mediated similar levels of gene transfer into mouse liver with the conventional Ad vectors. These results suggest that continued interaction of either the fiber with CAR or the penton base with αv integrin offers an effective route of virus entry into mouse liver in vivo. Inhibition of the interaction of both the fiber with CAR and the penton base with αv integrin is likely to be crucial to the development of targeted Ad vectors.

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Acknowledgements

We would like to thank Mr Jun Murai for his technical assistance. This work was supported by grants from the Ministry of Health, Labour and Welfare of Japan and a Grant-in-Aid for Scientific Research on Priority Areas (C).

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Authors and Affiliations

  1. Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Tokyo, Japan

    H Mizuguchi, N Koizumi, T Hosono, A Ishii-Watabe, E Uchida & T Hayakawa

  2. Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo, Japan

    N Koizumi, N Utoguchi & Y Watanabe

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  1. H Mizuguchi
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Mizuguchi, H., Koizumi, N., Hosono, T. et al. CAR- or αv integrin-binding ablated adenovirus vectors, but not fiber-modified vectors containing RGD peptide, do not change the systemic gene transfer properties in mice. Gene Ther 9, 769–776 (2002). https://doi.org/10.1038/sj.gt.3301701

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