Targeting adenoviral infection with basic fibroblast growth factor enhances gene delivery to vascular endothelial and smooth muscle cells

Academic Article

Abstract

  • Gene therapy is an attractive strategy for the treatment of a number of vascular diseases. Of the currently available vectors, the adenovirus has been most promising for in vivo gene delivery. However, the utility of this vector for gene transfer to vascular cells is limited by a direct toxic effect of the virus when administered at high doses. To help overcome this limitation, we aimed to develop a strategy to enable an enhancement in gene transfer while potentially keeping the concentration of virus used below that associated with toxicity. Because there are relatively few adenoviral receptors on vascular cells, we retargeted adenoviral infection to an alternate receptor, the fibroblast growth factor (FGF) receptor, which is expressed on both vascular endothelial and smooth muscle cells. We used a conjugate between basic FGF (FGF2) and the Fab fragment of a neutralizing monoclonal antibody against the knob region of the adenoviral fiber to redirect viral tropism. Retargeted adenoviral vectors (carrying the genes for luciferase or β-galactosidase) were used to infect human umbilical vein endothelial cells (HUVECs), human coronary artery endothelial cells (HCAECs) and human aortic smooth muscle cells (HASMCs). Infection with the retargeted vector resulted in enhancement of luciferase expression by 32.4 (± 6.6) fold, 4.55 (± 1.3) fold and 92.6 (± 2.6) fold in the HUVECs, HCAECs and HASMCs respectively. The use of Fab-FGF2 to retarget the β-galactosidase- encoding vector resulted in both an increase in the number of transduced cells and the level of gene expression per cell. The enhancement of luciferase gene transduction seen with FGF2 retargeting fell with time spent in confluent culture, as did FGF receptor expression, suggesting this strategy may permit selective targeting to rapidly proliferating cells. FGF2 retargeting of adenovirally mediated gene delivery significantly enhanced transduction of proliferating vascular cells, suggesting this strategy may permit high levels of transduction at doses of virus below those associated with acute toxicity.
  • Authors

    Published In

  • Tumor Targeting  Journal
  • Author List

  • Reynolds PN; Miller CR; Goldman CK; Doukas J; Sosnowski BA; Rogers BE; Gomez-Navarro J; Pierce GF; Curiel DT; Douglas JT
  • Start Page

  • 156
  • End Page

  • 168
  • Volume

  • 3
  • Issue

  • 3