A novel strategy to modify adenovirus tropism and enhance transgene delivery to activated vascular endothelial cells in vitro and in vivo

Ken Ichi Ogawara, Marianne G. Rots, Robbert J. Kok, Henk E. Moorlag, Anne Miek Van Loenen, Dirk K.F. Meijer, Hidde J. Haisma, Grietje Molema

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

To assess the possibilities of retargeting adenovirus to activated endothelial cells, we conjugated bifunctional polyethylene glycol (PEG) onto the adenoviral capsid to inhibit the interaction between viral knob and coxsackie-adenovirus receptor (CAR). Subsequently, we introduced an αv integrin-specific RGD peptide or E-selectin-specific antibody to the other functional group of the PEG molecule for the retargeting of the adenovirus to activated endothelial cells. In vitro studies showed that this approach resulted in the elimination of transgene transfer into CAR-positive cells, while at the same time specific transgene transfer to activated endothelial cells was achieved. PEGylated, retargeted adenovirus showed longer persistence in the blood circulation with area under plasma concentration-time curve (AUC) values increasing 12-fold compared to unmodified virus. Anti-E-selectin antibody-PEG-adenovirus selectively homed to inflamed skin in mice with a delayed-type hypersensitivity (DTH) inflammation, resulting in local expression of the reporter transgene luciferase. This is the first study showing the benefits of PEGylation on adenovirus behavior upon systemic administration. The approach described here can form the basis for further development of adenoviral gene therapy vectors with improved pharmacokinetics and increased efficiency and specificity of therapeutic gene transfer into endothelial cells in disease.

Original languageEnglish
Pages (from-to)433-443
Number of pages11
JournalHuman Gene Therapy
Volume15
Issue number5
DOIs
Publication statusPublished - May 1 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Ogawara, K. I., Rots, M. G., Kok, R. J., Moorlag, H. E., Van Loenen, A. M., Meijer, D. K. F., Haisma, H. J., & Molema, G. (2004). A novel strategy to modify adenovirus tropism and enhance transgene delivery to activated vascular endothelial cells in vitro and in vivo. Human Gene Therapy, 15(5), 433-443. https://doi.org/10.1089/10430340460745766