Publication

PDGF-receptor beta-targeted adenovirus redirects gene transfer from hepatocytes to activated stellate cells

Schoemaker, M. H., Rots, M. G., Beljaars, L., Ypma, A. Y., Jansen, P. L. M., Poelstra, K., Moshage, A. & Haisma, H. J., 2008, In : Molecular pharmaceutics. 5, 3, p. 399-406 8 p.

Research output: Contribution to journalArticleAcademicpeer-review

Chronic liver damage may lead to liver fibrosis. In this process, hepatic activated stellate cells are the key players. Thus, activated stellate cells are attractive targets for antifibrotic gene therapy. Recombinant, adenovirus is a promising vehicle for delivering therapeutic genes to liver cells. However, this vector has considerable tropism for hepatocytes and Kupffer cells. The aim of this study is therefore to retarget the adenovirus to the activated stellate cells while reducing its affinity for hepatocytes. We constructed a fusion protein with affinity for both the adenovirus and the platelet derived growth factor-receptor beta (PDGF-R beta). In contrast to other cells, the PDFG-R beta is highly expressed on activated stellate cells. The targeting moiety, the PDGF peptide CSRNLIDC, was cloned in front of the single-chain antibody fragment (S11) directed against the adenoviral knob. This fusion protein enhanced adenoviral gene transfer in both 3T3 fibroblasts and primary isolated activated rat stellate cells by 10-60-fold. A fusion protein with a scrambled PDGF peptide (CIDNLSRC) did not accomplish this effect. Importantly, the PDGF-R beta-retargeted adenovirus showed a 25-fold reduced tropism for primary rat hepatocytes. Our novel approach demonstrates that therapeutic genes can be selectively directed to stellate cells. This opens new possibilities for the treatment of liver fibrosis.

Original languageEnglish
Pages (from-to)399-406
Number of pages8
JournalMolecular pharmaceutics
Volume5
Issue number3
Publication statusPublished - 2008

    Keywords

  • scFv, liver fibrosis, gene targeting, PDGF-receptor, adenovirus, GROWTH-FACTOR RECEPTOR, FAT-STORING CELLS, CIRRHOTIC RAT LIVERS, FACTOR-KAPPA-B, FIBROSIS, APOPTOSIS, VECTORS, EXPRESSION, BINDING, CAR

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