Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA–protease interactions
- 作者：Judit Szé ; csi ; Rosybel Drury ; Vé ; ronique Josserand ; Marie-Pierre Grange ; Bertrand Boson ; Irene Hartl ; Richard Schneider ; Christian J. Buchholz ; Jean-Luc Coll ; Stephen J. Russell et al.
- 关键词：gene therapy ; matrix metalloproteinases ; hemagglutinin ; targeting ; retroviral vectors
- 刊名：Molecular Therapy
- 出版年：2006
- 期刊代码：177_15250016
- 类别：bio
- 出版时间：November 2006
- 卷：14
- 期：5
- 页码：735-744
- 文件大小：875 K
摘要
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.