TARGETING OF RETROVIRAL VECTORS THROUGH PROTEASE-SUBSTRATE INTERACTIONS

Targetable, injectable vectors would greatly facilitate the developmen t of in vivo gene therapy strategies. Viral and nonviral vectors can b e targeted through ligand-receptor interactions, but protease-substrat e interactions have not previously been exploited for vector targeting . Epidermal growth factor (EGF) was fused to a retroviral envelope gly coprotein via a cleavable linker comprising a factor Xa protease recog nition signal. Vector particles displaying the cleavable EGF domain co uld bind to EGF receptors on human cells but did not transfer their ge nes until they were cleaved by factor Xa protease, whereupon gene deli very proceeded normally. Proteolytic activation of receptor-targeted v ectors can therefore provide the basis for a novel two-step targeting strategy that nay facilitate efficient targeted in vivo delivery of th erapeutic genes.