Targeting vascular injury using Hantavirus-pseudotyped lentiviral vectors.

ABSTRACT

Restenosis is a pathological condition involving intimal hyperplasia and negative arterial remodeling. Gene therapy vectors have shown modest therapeutic effects, but the level of infectivity has been relatively poor. In the present study we have designed a modified lentiviral vector (LV) pseudotyped with a strain of Hantavirus (HTNV) to improve the transduction efficiency into vascular smooth muscle and endothelial cells in vitro and in vivo. In vivo studies using adult New Zealand White rabbits demonstrated that local delivery of HTNV-pseudotyped LV (2 x 10(7) TU) into balloon-injured carotid arteries led to highly efficient transduction into endothelial and smooth muscle cells more effectively than VSV-G-pseudotyped LV (2 x 10(7) TU) or replication-defective adenoviral vectors (1-1.5 x 10(9) pfu) as determined by beta-gal immunohistochemistry. Overexpression of extracellular superoxide dismutase in balloon-injured carotid arteries 6 weeks after LV administration resulted in a significant reduction (P = 0.0024) of the intima/media ratio (0.18 +/- 0.09; n = 4) compared to vehicle-infused carotid arteries (0.69 +/- 0.08; n = 7). No beta-gal immunostaining was detected in other systemic organs, including the spleen, liver, heart, lung, kidneys, and brain. Moreover, no changes in plasma alanine aminotransferase or aspartate aminotransferase were detected following LV administration. In all, these data show that LV pseudotyped with Hantaviral glycoproteins can be a useful vector for targeting therapeutic genes to the vasculature in vivo.