INCREASED IN-VITRO AND IN-VIVO GENE-TRANSFER BY ADENOVIRUS VECTORS CONTAINING CHIMERIC FIBER PROTEINS

Alteration of the natural tropism of adenovirus (Ad) will permit gene transfer into specific cell types and thereby greatly broaden the scop e of target diseases that can be treated by using Ad. We have construc ted two Ad vectors which contain modifications to the Ad fiber coat pr otein that redirect virus binding to either alpha(v) integrin [AdZ.F(R GD)] or heparan sulfate [AdZ.F(pK7)] cellular receptors. These vectors were constructed by a novel method involving E4 rescue of an E4-defic ient Ad with a transfer vector containing both the E4 region and the m odified fiber gene. AdZ.F(RGD) increased gene delivery to endothelial and smooth muscle cells expressing a, integrins. Likewise, AdZ.F(pK7) increased transduction 5- to 500-fold in multiple cell types lacking h igh levels of Ad fiber receptor, including macrophage, endothelial, sm ooth muscle, fibroblast, and T cells. In addition, AdZ.F(pK7) signific antly increased gene transfer in vivo to vascular smooth muscle cells of the porcine iliac artery following balloon angioplasty. These vecto rs may therefore be useful in gene therapy for vascular restenosis or for targeting endothelial cells in tumors. Although binding to the fib er receptor still occurs with these vectors, they demonstrate the feas ibility of tissue-specific receptor targeting in cells which express l ow levels of Ad fiber receptor.