TARGETING RETROVIRAL VECTORS TO VASCULAR-LESIONS BY GENETIC-ENGINEERING OF THE MOMLV GP70 ENVELOPE PROTEIN

Targeted gene delivery to vascular lesions is a major challenge in the development of gene therapy protocols for cardiovascular diseases, On e approach would be to enable retroviral vectors to accumulate at site s of vascular injury and enhance local vector concentration, An early step in wound repair is the adhesion of platelets to collagen exposed from damaged vasculature, Hence, the Moloney murine leukemia virus (Mo MLV) envelope (env) protein was engineered to incorporate a high-affin ity collagen-binding domain derived from von Willebrand clotting facto r, and expressed in Escherichia coli and in mammalian cells, The chime ric env protein bound tightly to collagen, and virions bearing this co llagen-binding env protein exhibited viral titers approaching those of virions expressing wild-type (WT) env protein, The chimeric virions w ere concentrated on collagen matrices, and they retained their infecti vity under conditions in which virions bearing WT env protein were was hed away, Targeted delivery of the chimeric env protein to injured mou se aorta and selective binding of the collagen-targeted virions to inj ured rabbit artery were observed, In comparative studies, vascular smo oth muscle cell transduction was demonstrated in catheter-injured caro tid arteries following infusion of collagen-targeted virions but not o f virions bearing WT env protein, Taken together, these observations d emonstrate the ability of collagen-targeted virions to localize gene d elivery to sites of vascular injury.