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Direct selection of targeted adenovirus vectors by random peptide display on the fiber knob

Gene Therapy volume 14, pages 1448–1460 (2007)Cite this article

Abstract

Targeting of gene transfer at the level of cell entry is one of the most attractive challenges in vector development. However, attempts to redirect adenovirus vectors to alternative receptors by engineering the capsid-coding region have shown limited success because proper targeting ligand–receptor systems on the cells of interest are generally unknown. Systematic approaches to generate adenovirus vectors targeting any given cell type need to be developed to achieve this goal. Here, we constructed an adenovirus library that was generated by a Cre-lox-mediated in vitro recombination between an adenoviral fiber-modified plasmid library and genomic DNA to display random peptides on a fiber knob. As proof of concept, we screened the adenovirus display library on a glioma cell line and observed selection of several particular peptide sequences. The targeted vector carrying the most frequently isolated peptide significantly enhanced gene transduction in the glioma cell line but not in many other cell lines. Because the insertion of a pre-selected peptide into a fiber knob often fails to generate an adenovirus vector, the selection of targeting peptides is highly useful in the context of the adenoviral capsid. This vector-screening system can facilitate the development of a targeted adenovirus vector for a variety of applications in medicine.

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Acknowledgements

This work was supported in part by a grant-in-aid for the 3rd Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan, grants-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan, and a grant-in-aid (#W81XWH-05-1-0035) from the Department of Defense of the United States. We thank Gary Quinn for useful discussion and Miwa Kushida and Atushi Kondo for technical help. Y Miura, K Hatanaka and T Nishimoto are awardees of a Research Resident Fellowship from the Foundation (Japan) for the Promotion of Science.

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Authors and Affiliations

  1. Genetics Division, National Cancer Center Research Institute, Tokyo, Japan

    Y Miura, K Yoshida, K Hatanaka, S Ohnami & T Yoshida

  2. Section for Studies on Host-Immune Response, National Cancer Center Research Institute, Tokyo, Japan

    T Nishimoto & K Aoki

  3. Department of Gastroenterology and Hematology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    M Asaka

  4. Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology and Surgery, and the Gene Therapy Center, The University of Alabama at Birmingham, Birmingham, AL, USA

    J T Douglas & D T Curiel

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  1. Y Miura
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Correspondence to K Aoki.

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Miura, Y., Yoshida, K., Nishimoto, T. et al. Direct selection of targeted adenovirus vectors by random peptide display on the fiber knob. Gene Ther 14, 1448–1460 (2007). https://doi.org/10.1038/sj.gt.3303007

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