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 Xia, H.
Right arrow Articles by Davidson, B. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xia, H.
Right arrow Articles by Davidson, B. L.

 Previous Article  |  Next Article 

Journal of Virology, December 2000, p. 11359-11366, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Recombinant Human Adenovirus: Targeting to the Human Transferrin Receptor Improves Gene Transfer to Brain Microcapillary Endothelium

Haibin Xia,1 Brian Anderson,1 Qinwen Mao,1 and Beverly L. Davidson1,2,*

Program in Gene Therapy, Departments of Internal Medicine1 and Neurology,2 University of Iowa College of Medicine, Iowa City, Iowa 52242

Received 23 June 2000/Accepted 30 August 2000

Some inborn errors of metabolism due to deficiencies of soluble lysosomal enzymes cause global neurodegenerative disease. Representative examples include the infantile and late infantile forms of the ceroid lipofuscinoses (CLN1 or CLN2 deficiency, respectively) and mucopolysaccharidoses type VII (MPS VII), a deficiency of beta -glucuronidase. Treatment of the central nervous system component of these disorders will require widespread protein or enzyme replacement, either through dissemination of the protein or through dissemination of a gene encoding it. We hypothesize that transduction of brain microcapillary endothelium (BME) with recombinant viral vectors, with secretion of enzyme product basolaterally, could allow for widespread enzyme dissemination. To achieve this, viruses should be modified to target the BME. This requires (i) identification of a BME-resident target receptor, (ii) identification of motifs targeted to that molecule, (iii) the construction of modified viruses to allow for binding to the target receptor, and (iv) demonstrated transduction of receptor-expressing cells. In proof of principal experiments, we chose the human transferrin receptor (hTfR), a molecule found at high density on human BME. A nonamer phage display library was panned for motifs which could bind hTfR. Forty-three clones were sequenced, most of which contained an AKxxK/R, KxKxPK/R, or KxK motif. Ten peptides representative of the three motifs were cloned into the HI loop of adenovirus type 5 fiber. All motifs tested retained their ability to trimerize and bind transferrin receptor, and seven allowed for recombinant adenovirus production. Importantly, the fiber-modified viruses facilitated increased gene transfer (2- to 34-fold) to hTfR expressing cell lines and human brain microcapillary endothelia expressing high levels of endogenous receptor. Our data indicate that adenoviruses can be modified in the HI loop for expanded tropism to the hTfR.

* Corresponding author. Mailing address: Department of Internal Medicine and Neurology, 200 EMRB, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 353-5511. Fax: (319) 353-5572. E-mail: beverly-davidson{at}uiowa.edu.

Journal of Virology, December 2000, p. 11359-11366, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Belousova, N., Mikheeva, G., Gelovani, J., Krasnykh, V. (2008). Modification of Adenovirus Capsid with a Designed Protein Ligand Yields a Gene Vector Targeted to a Major Molecular Marker of Cancer. J. Virol. 82: 630-637 [Abstract] [Full Text]  
  • Lamfers, M. L.M., Idema, S., Bosscher, L., Heukelom, S., Moeniralm, S., van der Meulen-Muileman, I. H., Overmeer, R. M., van der Valk, P., van Beusechem, V. W., Gerritsen, W. R., Vandertop, W. P., Dirven, C. M.F. (2007). Differential Effects of Combined Ad5-{Delta}24RGD and Radiation Therapy in In vitro versus In vivo Models of Malignant Glioma. Clin. Cancer Res. 13: 7451-7458 [Abstract] [Full Text]  
  • Palermo, L. M., Hafenstein, S. L., Parrish, C. R. (2006). Purified feline and canine transferrin receptors reveal complex interactions with the capsids of canine and feline parvoviruses that correspond to their host ranges.. J. Virol. 80: 8482-8492 [Abstract] [Full Text]  
  • Meier, O., Gastaldelli, M., Boucke, K., Hemmi, S., Greber, U. F. (2005). Early Steps of Clathrin-Mediated Endocytosis Involved in Phagosomal Escape of Fc{gamma} Receptor-Targeted Adenovirus. J. Virol. 79: 2604-2613 [Abstract] [Full Text]  
  • Baker, A. H., Kritz, A., Work, L. M., Nicklin, S. A. (2005). Cell-selective viral gene delivery vectors for the vasculature. Exp Physiol 90: 27-31 [Abstract] [Full Text]  
  • Fontana, L., Nuzzo, M., Urbanelli, L., Monaci, P. (2003). General Strategy for Broadening Adenovirus Tropism. J. Virol. 77: 11094-11104 [Abstract] [Full Text]  
  • Meier, O., Boucke, K., Hammer, S. V., Keller, S., Stidwill, R. P., Hemmi, S., Greber, U. F. (2002). Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. JCB 158: 1119-1131 [Abstract] [Full Text]  
  • Belousova, N., Krendelchtchikova, V., Curiel, D. T., Krasnykh, V. (2002). Modulation of Adenovirus Vector Tropism via Incorporation of Polypeptide Ligands into the Fiber Protein. J. Virol. 76: 8621-8631 [Abstract] [Full Text]  
  • Dmitriev, I. P., Kashentseva, E. A., Curiel, D. T. (2002). Engineering of Adenovirus Vectors Containing Heterologous Peptide Sequences in the C Terminus of Capsid Protein IX. J. Virol. 76: 6893-6899 [Abstract] [Full Text]  
  • Law, L. K., Davidson, B. L. (2002). Adenovirus Serotype 30 Fiber Does Not Mediate Transduction via the Coxsackie-Adenovirus Receptor. J. Virol. 76: 656-661 [Abstract] [Full Text]  
  • Pereboev, A., Pereboeva, L., Curiel, D. T. (2001). Phage Display of Adenovirus Type 5 Fiber Knob as a Tool for Specific Ligand Selection and Validation. J. Virol. 75: 7107-7113 [Abstract] [Full Text]  
  • Lam, P. Y.P., Breakefield, X. O. (2001). Potential of gene therapy for brain tumors. Hum Mol Genet 10: 777-787 [Abstract] [Full Text]  
  • White, S. J., Nicklin, S. A., Sawamura, T., Baker, A. H. (2001). Identification of Peptides That Target the Endothelial Cell-Specific LOX-1 Receptor. Hypertension 37: 449-455 [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»