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

Belousova, Natalya and Mikheeva, Galina and Xiong, Chiyi and Soghomonian, Suren and Young, Daniel and Le Roux, Lucia and Naff, Katherine and Bidaut, Luc and Wei, Wei and Li, Chun and Gelovani, Juri and Krasnykh, Victor (2010) Development of a targeted gene vector platform based on simian adenovirus serotype 24. Journal of Virology, 84 (19). pp. 10087-10101. ISSN 0022-538X

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Item Type:Article
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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. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Keywords:blood clotting factor 10, epidermal growth factor receptor 2, neutralizing antibody, cytokine, ERBB2 protein, human, primer DNA, virus antibody, virus DNA, animal experiment, animal model, article, controlled study, flow cytometry, gene expression, gene targeting, gene transfer, gene vector, human, human cell, in vitro study, Kupffer cell, mouse, nonhuman, priority journal, protein expression, serotype, simian virus, virion, Western blotting, animal, biosynthesis, C57BL mouse, classification, female, gene therapy, genetics, Human adenovirus, ice cover, immunology, liver, Lung Neoplasms, metabolism, nucleotide sequence, secondary, serotyping, species difference, tumor cell line, virology, Adenoviridae, Animalia, Murinae, Simiae, Simian adenovirus, Adenoviruses, Human, Adenoviruses, Simian, Animals, Antibodies, Neutralizing, Antibodies, Viral, Base Sequence, Cell Line, Tumor, Cytokines, DNA Primers, DNA, Viral, Factor X, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Humans, Kupffer Cells, Mice, Mice, Inbred C57BL, Receptor, ErbB-2, Species Specificity
Divisions:College of Science > School of Computer Science
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ID Code:24136
Deposited On:05 Apr 2017 09:39

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