Analysis of cell-specific promoters for viral gene therapy targeted at the vascular endothelium

Nicklin, S., Reynolds, P., Brosnan, M., White, S., Curiel, D., Dominiczak, A. and Baker, A. (2001) Analysis of cell-specific promoters for viral gene therapy targeted at the vascular endothelium. Hypertension, 38(1), pp. 65-70. (doi:10.1161/01.HYP.38.1.65)

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Abstract

The use of viral vectors for vascular gene therapy targeted at the endothelium is limited by the promiscuous tropism of vectors and nonspecificity of viral promoters, resulting in high-level transgene expression in multiple tissues. To evaluate suitable endothelial cell (EC)–specific promoters for vascular gene therapy, we directly compared the ability of the fms-like tyrosine kinase-1 (FLT-1), intercellular adhesion molecule-2 (ICAM-2), and von Willebrand factor (vWF) promoters to drive EC-restricted transcription after cloning into adenoviral vectors upstream of lacZ. Vastly different expression profiles were observed. Whereas both FLT-1 and ICAM-2 promoters generated transgene expression levels similar to cytomegalovirus in ECs in vitro, vWF expression levels were extremely low. Analysis of non-EC types revealed that ICAM-2 but not FLT-1 evoked leaky transgene expression, thus identifying FLT-1 as the most selective promoter. With an ex vivo human gene therapy model, the FLT-1 promoter demonstrated EC-specific transgene expression in intact human vein but no detectable expression from infected exposed smooth muscle cells in EC-denuded vein. Furthermore, when adenoviruses were systemically administered to mice, the FLT-1 promoter demonstrated extremely low-level gene expression in the liver, the major target organ for adenoviral transduction in vivo. This study highlights the potential of using the FLT-1 promoter for local and systemic human gene therapy in hypertension and its complications.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dominiczak, Professor Anna and Nicklin, Professor Stuart and Baker, Professor Andrew
Authors: Nicklin, S., Reynolds, P., Brosnan, M., White, S., Curiel, D., Dominiczak, A., and Baker, A.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X

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