This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Korokhov, N.
Right arrow Articles by Krasnykh, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Korokhov, N.
Right arrow Articles by Krasnykh, V.

Next Article 

Journal of Virology, December 2003, p. 12931-12940, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.12931-12940.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeting of Adenovirus via Genetic Modification of the Viral Capsid Combined with a Protein Bridge

Nikolay Korokhov,1 Galina Mikheeva,1 Alexander Krendelshchikov,1 Natalya Belousova,2 Vera Simonenko,2 Valentina Krendelshchikova,2 Alexander Pereboev,2 Alexander Kotov,3 Olga Kotova,3 Pierre L. Triozzi,4 Wayne A. Aldrich,4 Joanne T. Douglas,2 Kin-Ming Lo,5 Papia T. Banerjee,5 Stephen D. Gillies,5 David T. Curiel,2* and Victor Krasnykh1,2

VectorLogics, Inc.,1 Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery, and Gene Therapy Center,2 Vector and Vaccine Production Facility at the Comprehensive Cancer Center,3 Division of Hematology-Oncology, University of Alabama at Birmingham, Alabama 35294,4 EMD Lexigen Research Center Corporation, Billerica, Massachusetts 018215

Received 8 May 2003/ Accepted 4 September 2003

A potential barrier to the development of genetically targeted adenovirus (Ad) vectors for cell-specific delivery of gene therapeutics lies in the fact that several types of targeting protein ligands require posttranslational modifications, such as the formation of disulfide bonds, which are not available to Ad capsid proteins due to their nuclear localization during assembly of the virion. To overcome this problem, we developed a new targeting strategy, which combines genetic modifications of the Ad capsid with a protein bridge approach, resulting in a vector-ligand targeting complex. The components of the complex associate by virtue of genetic modifications to both the Ad capsid and the targeting ligand. One component of this mechanism of association, the Fc-binding domain of Staphylococcus aureus protein A, is genetically incorporated into the Ad fiber protein. The ligand is comprised of a targeting component fused with the Fc domain of immunoglobulin, which serves as a docking moiety to bind to these genetically modified fibers during the formation of the Ad-ligand complex. The modular design of the ligand solves the problem of structural and biosynthetic compatibility with the Ad and thus facilitates targeting of the vector to a variety of cellular receptors. Our study shows that targeting ligands incorporating the Fc domain and either an anti-CD40 single-chain antibody or CD40L form stable complexes with protein A-modified Ad vectors, resulting in significant augmentation of gene delivery to CD40-positive target cells. Since this gene transfer is independent of the expression of the native Ad5 receptor by the target cells, this strategy results in the derivation of truly targeted Ad vectors suitable for tissue-specific gene therapy.

* Corresponding author. Mailing address: Gene Therapy Center, The University of Alabama at Birmingham, 901 19th St. South, BMR2 508, Birmingham, AL 35294. Phone: (205) 934-8627. Fax: (205) 975-7476. E-mail: David.Curiel{at}ccc.uab.edu.

Journal of Virology, December 2003, p. 12931-12940, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.12931-12940.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Granio, O., Porcherot, M., Corjon, S., Kitidee, K., Henning, P., Eljaafari, A., Cimarelli, A., Lindholm, L., Miossec, P., Boulanger, P., Hong, S.-S. (2009). Improved Adenovirus Type 5 Vector-Mediated Transduction of Resistant Cells by Piggybacking on Coxsackie B-Adenovirus Receptor-Pseudotyped Baculovirus. J. Virol. 83: 6048-6066 [Abstract] [Full Text]  
  • Tanaka, T., Huang, J., Hirai, S., Kuroki, M., Kuroki, M., Watanabe, N., Tomihara, K., Kato, K., Hamada, H. (2006). Carcinoembryonic Antigen-Targeted Selective Gene Therapy for Gastric Cancer through FZ33 Fiber-Modified Adenovirus Vectors.. Clin. Cancer Res. 12: 3803-3813 [Abstract] [Full Text]  
  • Komarova, S., Kawakami, Y., Stoff-Khalili, M. A., Curiel, D. T., Pereboeva, L. (2006). Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses.. Molecular Cancer Therapeutics 5: 755-766 [Abstract] [Full Text]  
  • Krebs, P., Scandella, E., Odermatt, B., Ludewig, B. (2005). Rapid Functional Exhaustion and Deletion of CTL following Immunization with Recombinant Adenovirus. J. Immunol. 174: 4559-4566 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»