Targeting an adenoviral gene vector to cytokine-activated vascular endothelium via E-selectin.
We have aimed at selective gene delivery to vascular endothelial cells (EC) at sites of inflammation, by targeting E-selectin, a surface adhesion molecule that is only expressed by activated EC. An anti-E-selectin mAb, 1.2B6, was complexed with the adenovirus vector AdZ.FLAG (expressing the FLAG peptide) by conjugating it to an anti-FLAG mAb. Gene transduction of cultured EC was increased 20-fold compared with AdZ.FLAG complexed with a control bsAb providing EC were activated by cytokines. The anti-E-selectin-complexed vector transduced 29 +/- 9% of intimal EC in segments of pig aorta cultured with cytokines ex vivo, compared with less than 0.1% transduced with the control construct (P < 0.05). This strategy could be developed to target endothelium in inflammation with genes capable of modifying the inflammatory response.
Harari
O A
OA
BHF Cardiovascular Medicine Unit, National Heart and Lung Institute, London, UK.
Wickham
T J
TJ
Stocker
C J
CJ
Kovesdi
I
I
Segal
D M
DM
Huehns
T Y
TY
Sarraf
C
C
Haskard
D O
DO
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics; D001011:Aorta; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D019040:E-Selectin / Q000276:immunology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D015870:Gene Expression; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D008213:Lymphocyte Activation; D013552:Swine; D014162:Transfection / Q000379:methods; D014657:Vasculitis / Q000628:therapy*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D019040:E-Selectin