Development of a targeted gene vector platform based on simian adenovirus serotype 24

Natalya Belousova, Galina Mikheeva, Chiyi Xiong, Suren Soghomonian, Daniel Young, Lucia Le Roux, Katherine Naff, Luc Bidaut, Wei Wei, Chun Li, Juri Gelovani, Victor Krasnykh

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    10 Citations (Scopus)

    Abstract

    Efforts to develop adenovirus vectors suitable for genetic interventions in humans have identified three major limitations of the most frequently used vector prototype, human adenovirus serotype 5 (Ad5). These limitations-widespread preexisting anti-Ad5 immunity in humans, the high rate of transduction of normal nontarget tissues, and the lack of target-specific gene delivery-justify the exploration of other Ad serotypes as vector prototypes. In this paper, we describe the development of an alternative vector platform using simian Ad serotype 24 (sAd24). We found that sAd24 virions formed unstable complexes with blood coagulation factor X and, because of that, transduced the liver and other organs at low levels when administered intravenously. The overall pattern of biodistribution of sAd24 particles was similar, however, to that of Ad5, and the intravenously injected sAd24 was cleared by Kupffer cells, leading to their depletion. We modified the virus's fiber protein to design a Her2-specific derivative of sAd24 capable of infecting target human tumor cells in vitro. In the presence of neutralizing anti-Ad5 antibodies, Her2-mediated infection with targeted sAd24 compared favorably to that with the Ad5-derived vector. When used to target Her2-expressing tumors in animals, this fiber-modified vector achieved a higher level of gene transfer to metastasis-containing murine lungs than to tumor-free lungs. In aggregate, these studies provide important insights into sAd24 biology, identify its advantages and limitations as a vector prototype, and are thus essential for further development of an sAd24-based gene delivery platform.

    Original languageEnglish
    Pages (from-to)10087-10101
    Number of pages15
    JournalJournal of Virology
    Volume84
    Issue number19
    DOIs
    Publication statusPublished - Oct 2010

    Keywords

    • Type 2 fiber trimmers
    • Cellular receptor
    • In vivo
    • Chimpanzee adenoviruses
    • Attachment protein
    • Affibody molecule
    • Escherichia coli
    • Immune responses
    • Ovarian cancer
    • Binding site

    Cite this

    Belousova, N., Mikheeva, G., Xiong, C., Soghomonian, S., Young, D., Le Roux, L., Naff, K., Bidaut, L., Wei, W., Li, C., Gelovani, J., & Krasnykh, V. (2010). Development of a targeted gene vector platform based on simian adenovirus serotype 24. Journal of Virology, 84(19), 10087-10101. https://doi.org/10.1128/JVI.02425-09