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Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

Gene Therapy volume 16, pages 1050–1057 (2009)Cite this article

Abstract

Fiber-substituted adenovirus (Ad) vectors containing fibers of Ad serotype 35 (AdF35) efficiently transduce a variety of human cells because their receptor, human CD46, is ubiquitously expressed on almost all nucleated cells. However, the ubiquitous expression of CD46 might lead to unexpected transduction in untargeted organs. In this study, we developed fiber-modified AdF35 vectors with an integrin-binding Arg-Gly-Asn (RGD) peptide incorporated into the FG, HI or IJ loop, which have been identified as important regions for binding to CD46. Incorporation of foreign peptides into these loops does not inhibit trimerization of the fibers. In CD46-negative cells, fiber-mutant AdF35 vectors containing an RGD peptide in the FG or HI loop showed 6- to 30-fold higher transduction efficiencies in an RGD-peptide-dependent manner than the unmodified AdF35 vectors. In contrast, in CD46-positive cells, insertion of foreign peptides markedly reduced the transduction efficiencies of the AdF35 vectors, indicating that insertion of foreign peptides significantly inhibits binding to CD46. In particular, CD46-mediated transduction was completely diminished by insertion of foreign peptides into the HI loop. Our findings indicate that HI loop is the most suitable domain to mediate a foreign peptide-dependent and CD46-independent transduction by incorporation of foreign peptides into the Ad35 fiber knob.

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Acknowledgements

This work was supported in part by grants for Research on Publicly Essential Drugs and Medical Devices of The Japan Health Sciences Foundation, and The Uehara Memorial Foundation.

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Authors and Affiliations

  1. Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan

    H Matsui, F Sakurai, S Kurachi, K Tashiro, K Sugio, K Kawabata & H Mizuguchi

  2. Department of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    H Matsui, K Sugio & H Mizuguchi

  3. Department of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    S Kurachi, K Tashiro & K Yamanishi

  4. National Institute of Biomedical Innovation, Osaka, Japan

    K Yamanishi

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  1. H Matsui
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Matsui, H., Sakurai, F., Kurachi, S. et al. Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob. Gene Ther 16, 1050–1057 (2009). https://doi.org/10.1038/gt.2009.65

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