Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA-protease interactions

Judit Szécsi, Rosybel Drury, Véronique Josserand, Marie Pierre Grange, Bertrand Boson, Irene Hartl, Richard Schneider, Christian J. Buchholz, Jean Luc Coll, Stephen J. Russell, François Loïc Cosset, Els Verhoeyen

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

We report here a targeting method that exploits the expression pattern of cell surface proteases to induce gene delivery to specific tissues. We describe retroviral vectors harboring modified surface glycoproteins derived from an avian influenza virus hemagglutinin (HA) for which the cell entry properties, dependent on HA cleavage by producer cells, were conditionally blocked at a postbinding step by insertion of matrix metalloproteinase (MMP) substrates. We demonstrate that such vectors induce gene transfer, both in vitro and in mice harboring human tumor xenografts, only through contact with target cells expressing MMPs that cleave the substrate introduced into the recombinant HA. This selective gene transfer in MMP-rich cells was specifically inhibited by 1,10-phenanthroline, a broad-range MMP inhibitor. Importantly, such MMP-activatable vectors selectively transduced MMP-rich cells in heterogeneous populations containing MMP-rich and MMP-poor cells. These vectors will allow useful gene transfer applications into target cells exhibiting specific protease activities.

Original languageEnglish (US)
Pages (from-to)735-744
Number of pages10
JournalMolecular Therapy
Volume14
Issue number5
DOIs
StatePublished - Nov 1 2006

    Fingerprint

Keywords

  • gene therapy
  • hemagglutinin
  • matrix metalloproteinases
  • retroviral vectors
  • targeting

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Szécsi, J., Drury, R., Josserand, V., Grange, M. P., Boson, B., Hartl, I., Schneider, R., Buchholz, C. J., Coll, J. L., Russell, S. J., Cosset, F. L., & Verhoeyen, E. (2006). Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA-protease interactions. Molecular Therapy, 14(5), 735-744. https://doi.org/10.1016/j.ymthe.2006.04.007