Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin (HA) through HA-protease interactions.
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.
Szécsi
Judit
J
INSERM U758, 69364 Lyon, France.
Drury
Rosybel
R
Josserand
Véronique
V
Grange
Marie-Pierre
MP
Boson
Bertrand
B
Hartl
Irene
I
Schneider
Richard
R
Buchholz
Christian J
CJ
Coll
Jean-Luc
JL
Russell
Stephen J
SJ
Cosset
François-Loïc
FL
Verhoeyen
Els
E
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics*; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods*; D013379:Substrate Specificity
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D015951:Factor Xa; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C039814:hemagglutinin-protease