A genetically modified adenoviral vector exhibits enhanced gene transfer of human smooth muscle cells

Adenoviral vector-based gene therapy is a promising approach for the treatm ent of restenosis postangioplasty. However, a high concentration of adenovi ral vector can cause cellular activation, damage, and an enhanced immune re sponse. One approach to solving this problem is to increase gene transfer e fficiency by directing adenoviral vector entry via an alternate receptor sy stem. We have constructed an adenoviral vector, Av9LacZ, that encodes the b eta -galactosidase gene and contains a chimeric fiber protein that redirect s viral vector binding to the Ad3 adenoviral receptor on the host cell. We examined the ability of Av9LacZ to transduce primary human smooth muscle ce lls (SMC) and found that it showed a 10- to 15-fold higher transduction eff iciency when compared to the prototypic adenoviral vector currently used fo r preclinical and clinical studies. While both vectors were able to transdu ce rabbit, pig and monkey SMCs, the genetically modified vector transduced human SMC with much higher efficiency. SMC obtained from the aorta, coronar y, renal, popliteal and pulmonary arteries were all efficiently transduced by Av9LacZ. Consistent with the data obtained from cultured cells, Av9LacZ also transduced fresh human arterial tissues considerably more efficiently than Av1LacZ. We conclude that the large discrepancy between transduction o f animal and human cells by conventional vectors supports a cautious extrap olation of the results of in vivo animal studies to man. Furthermore, the g enetically modified AV9 vector may deliver better efficacy and studies in l arge animal models with this vector could be more predictive of therapeutic efficacy in the treatment of human restenosis. Copyright (C) 2001 S. Karge r AG, Basel.