Targeting of retroviral vectors through protease-substrate interactions.
Targetable, injectable vectors would greatly facilitate the development of in vivo therapy strategies. Viral and nonviral vectors can be targeted through ligand-receptor interactions, but protease-substrate interactions have not previously been exploited for vector targeting. Epidermal growth factor (EGF) was fused to a retroviral envelope glycoprotein via a cleavable linker comprising a factor Xa protease recognition signal. Vector particles displaying the cleavable EGF domain could bind to EGF receptors on human cells but did not transfer their genes until they were cleaved by factor Xa protease, whereupon gene delivery proceeded normally. Proteolytic activation of receptor-targeted vectors can therefore provide the basis for a novel two-step targeting strategy that may facilitate efficient targeted in vivo delivery of therapeutic genes.
Nilson
B H
BH
Cambridge Centre for Protein Engineering, MRC Centre, UK.
Morling
F J
FJ
Cosset
F L
FL
Russell
S J
SJ
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004274:DNA, Recombinant / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics* / Q000378:metabolism; D013379:Substrate Specificity
D004274:DNA, Recombinant; D015686:Gene Products, env; D008024:Ligands; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D010450:Endopeptidases; D015951:Factor Xa