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Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers

Gene Therapy volume 6, pages 1520–1535 (1999)Cite this article

Abstract

Recombinant adenoviral vectors are broadly applied in gene therapy protocols. However, adenovector-mediated gene transfer has limitations in vivo. One of these is the low gene transfer rate into organs other than the liver after systemic intravenous vector injection. Local direct injection into the target organ has been used as one possible solution, but increases necessary equipment and methodology and is traumatic to the target. Wild-type adenovirus infection as well as adenovector-mediated gene transfer depends on virus interaction with the Coxsackie adenovirus receptor (CAR) mediating virus attachment to the cell surface, and on interaction with αvβ3 and αvβ5 integrins mediating virus entry into the cell. In order to assess the receptor-associated potential of different tissues to act as adenovector targets, we have therefore determined CAR and αv-integrin expression in multiple organs from different species. In addition, we have newly determined several human, rat, pig and dog CAR-mRNA sequences. Sequence comparison and structural analyses of known and of newly determined sequences suggests a potential adenovirus binding site between amino acids 29 and 128 of the CAR. With respect to the virus receptor expression patterns we found that CAR-mRNA expression was extremely variable between different tissues, with the highest levels in the liver, whereas αv-integrin expression was far more homogenous among different organs. Both CAR and αv-integrin showed similar expression patterns among different species. There was no correlation, however, between the adenovector expression patterns after intravenous, intracardiac and aortic root injection, respectively, and the virus receptor patterns. In summary, many organs carry both receptors required to make them potential adenovector targets. In sharp contrast, their actual targeting clearly indicates that adenovirus receptor expression is necessary but not sufficient for vector transfer after systemic injection. The apparently very important role of anatomical barriers, in particular the endothelium, requires close attention when developing non-traumatic, organ-specific gene therapy protocols.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft through a Heisenberg fellowship to WP (378/2–1 and 378/2–2). The project was also supported by a grant from The Netherlands Heart Foundation, the Centeon Pharmaceutical Company, and by the Cardiovascular Research Center at the University Hospital Benjamin Franklin, Freie Universität Berlin. We thank C Riebeling (University Hospital Benjamin Franklin) for assistance with the empirical structure analysis.

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Authors and Affiliations

  1. Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Freie Universität, Berlin, Germany

    H Fechner, H Wang, X Wang, M Pauschinger, H-P Schultheiss & W Poller

  2. Institute for Experimental Haematology and Transfusion Medicine, Haemophilia Center, Georg-August-Universität Bonn, Germany

    A Haack

  3. Department of Biochemistry, COEUR, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands

    K Eizema & J M J Lamers

  4. Department of Pharmacology, COEUR, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands

    R G Schoemaker & R van Veghel

  5. Department of Pathology, COEUR, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands

    A B Houtsmuller

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Fechner, H., Haack, A., Wang, H. et al. Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers. Gene Ther 6, 1520–1535 (1999). https://doi.org/10.1038/sj.gt.3301030

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