M. Palasis et al., Analysis of adenoviral transport mechanisms in the vessel wall and optimization of gene transfer using local delivery catheters, HUM GENE TH, 11(2), 2000, pp. 237-246
Local delivery devices have been used for adenovirus-mediated gene transfer
to the arterial wall for the potential treatment of vascular proliferative
diseases. However, low levels of adenoviral gene expression in vascular sm
ooth muscle cells may pose a serious limitation to the success of these pro
cedures in the clinic. In this study, we examined the mechanisms controllin
g adenoviral transport to the vessel wall, using both hydrogel-coated and i
nfusion-based local delivery catheters, with the goal of enhancing in vivo
gene transfer under clinically relevant delivery conditions. The following
delivery parameters were tested in vivo: applied transmural pressure, viral
solution volume and concentration, and delivery time. We found that viral
particles are transported into the vessel wall in a manner consistent with
diffusion rather than pressure-driven convection. Consistent with diffusion
, viral concentration was shown to be the key variable for viral transport
in the vessel wall and thus gene expression in vascular smooth muscle cells
. A transduction level of 17.8 +/- 3.2% was achieved by delivering a low vo
lume of concentrated adenoviral beta-galactosidase solution through an infu
sion balloon catheter at low pressure without an adverse effect on medial c
ellularity. Under these conditions, effective gene transfer was accomplishe
d within a clinically relevant time frame of 2 min, indicating that longer
delivery times may not be necessary to achieve efficient gene transfer.