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

27 Citations (Scopus)

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 2006

Fingerprint

Hemagglutinins
Matrix Metalloproteinases
Genes
Peptide Hydrolases
Influenza in Birds
Matrix Metalloproteinase Inhibitors
hemagglutinin-protease
Membrane Glycoproteins
Orthomyxoviridae
Heterografts
Population

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Szécsi, J., Drury, R., Josserand, V., Grange, M. P., Boson, B., Hartl, I., ... 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

Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA-protease interactions. / Szécsi, Judit; Drury, Rosybel; Josserand, Véronique; Grange, Marie Pierre; Boson, Bertrand; Hartl, Irene; Schneider, Richard; Buchholz, Christian J.; Coll, Jean Luc; Russell, Stephen J; Cosset, François Loïc; Verhoeyen, Els.

In: Molecular Therapy, Vol. 14, No. 5, 11.2006, p. 735-744.

Research output: Contribution to journalArticle

Szécsi, J, Drury, R, Josserand, V, Grange, MP, Boson, B, Hartl, I, Schneider, R, Buchholz, CJ, Coll, JL, Russell, SJ, Cosset, FL & Verhoeyen, E 2006, 'Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA-protease interactions', Molecular Therapy, vol. 14, no. 5, pp. 735-744. https://doi.org/10.1016/j.ymthe.2006.04.007
Szécsi, Judit ; Drury, Rosybel ; Josserand, Véronique ; Grange, Marie Pierre ; Boson, Bertrand ; Hartl, Irene ; Schneider, Richard ; Buchholz, Christian J. ; Coll, Jean Luc ; Russell, Stephen J ; Cosset, François Loïc ; Verhoeyen, Els. / Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA-protease interactions. In: Molecular Therapy. 2006 ; Vol. 14, No. 5. pp. 735-744.
@article{939271e3a4a14ef28f2a8ee17d65dbb0,
title = "Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA-protease interactions",
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.",
keywords = "gene therapy, hemagglutinin, matrix metalloproteinases, retroviral vectors, targeting",
author = "Judit Sz{\'e}csi and Rosybel Drury and V{\'e}ronique Josserand and Grange, {Marie Pierre} and Bertrand Boson and Irene Hartl and Richard Schneider and Buchholz, {Christian J.} and Coll, {Jean Luc} and Russell, {Stephen J} and Cosset, {Fran{\cc}ois Lo{\"i}c} and Els Verhoeyen",
year = "2006",
month = "11",
doi = "10.1016/j.ymthe.2006.04.007",
language = "English (US)",
volume = "14",
pages = "735--744",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA-protease interactions

AU - Szécsi, Judit

AU - Drury, Rosybel

AU - Josserand, Véronique

AU - Grange, Marie Pierre

AU - Boson, Bertrand

AU - Hartl, Irene

AU - Schneider, Richard

AU - Buchholz, Christian J.

AU - Coll, Jean Luc

AU - Russell, Stephen J

AU - Cosset, François Loïc

AU - Verhoeyen, Els

PY - 2006/11

Y1 - 2006/11

N2 - 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.

AB - 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.

KW - gene therapy

KW - hemagglutinin

KW - matrix metalloproteinases

KW - retroviral vectors

KW - targeting

UR - http://www.scopus.com/inward/record.url?scp=33748755378&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748755378&partnerID=8YFLogxK

U2 - 10.1016/j.ymthe.2006.04.007

DO - 10.1016/j.ymthe.2006.04.007

M3 - Article

VL - 14

SP - 735

EP - 744

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 5

ER -