Visit our Expo - Redox and Inflammation signaling 2012

VIII. Inflammation specific signaling Poster VIII, 16
Redirecting adenovirus encoding dominant-negative inhibitor kappaB to inflamed
endothelial cells inhibits endothelial gene expression
J.M. Ku#do1, S.A. Asgeirsdottir1, A.R. Bellu2, M.G. Rots2, K.I. Ogawara3, T. Peneder1,
C. Trautwein4, H. Haisma2, and G. Molema1
University Medical Center Groningen, University of Groningen, The Netherlands;
1Department of Pathology and Laboratory Medicine, Medical Biology Section,
Hanzeplein 1, 9713 GZ Groningen, j.m.kuldo@med.umcg.nl; 2Department of
Therapeutic Gene Modulation; 3Department of Pharmaceutics, Faculty of
Pharmaceutical Sciences, Okayama University, Japan; 4Medical School of Hanover,
Germany
In glomerulonephritis endothelium expresses inflammatory molecules responsible for harmful
leukocyte infiltration. We propose that inhibition of expression of a broad spectrum of genes
by endothelial cells will inhibit disease progression by strong suppression of leukocyte
recruitment into the kidney. To accomplish this multiple gene inhibition, we used an
adenovirus encoding a therapeutic transgene that interferes with nuclear factor kappaB
signaling, a major pathway involved in inflammatory gene expression control. For retargeting
to the activated endothelial cells, we introduced endothelial cell-specific anti-E-selectin or
anti-VCAM-1 antibody-polyethylene glycol (PEG) modifications and studied effects of
constructs in endothelial and messangial cells in vitro, as well as in vivo in mouse model of
glomerulonephritis. In vitro retargeted adenoviruses selectively infected cytokine-activated
endothelial cell and no transgene was detected in (activated or non-activated) messangial
cells. E-selectin directed adenovirus was able to deliver more transgene to activated
endothelium than VCAM-1 directed virus. In vivo, PEGylated, anti-E-selectin-retargeted
adenovirus selectively homed to glomeruli in glomerulonephritis, resulting in downregulation
of inflammatory genes at two days after start of disease. These studies demonstrate the
potential of tropism-modified adenovirus to deliver therapeutic genes to endothelial cells in
inflammation.
- 300 -