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Rheumatology Advance Access published online on March 9, 2005
Rheumatology, doi:10.1093/rheumatology/keh590
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received November 10, 2004
Accepted January 28, 2005

Original Papers

Disease- and cell-type-specific transcriptional targeting of vectors for osteoarthritis gene therapy: further development of a clinical canine model

S. E. Campbell 1, D. Bennett 1, L. Nasir 1, E. A. Gault 1, and D. J. Argyle 2*

1 Molecular Therapeutics Research Group, Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK
2 University of Wisconsin Comparative Oncology Program, Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706-1102, USA

* To whom correspondence should be addressed.
D. J. Argyle, E-mail: argyled{at}svm.vetmed.wisc.edu


  Abstract

Objectives. The potential for undesirable systemic effects related to constitutive expression of certain therapeutic transgenes may be limited through the development of transcriptionally targeted disease- and cell-type-specific vectors. The objective of this study was to analyse the canine matrix metalloproteinase-9 (MMP-9) promoter and deletion constructs for its ability to drive expression in response to pro-inflammatory cytokines (interleukin-1{beta} and tumour necrosis factor-{alpha}).

Methods. Initial analysis of MMP-9 deletion constructs was made using a luciferase reporter system. The promoter was subsequently engineered to incorporate multiple NF-{kappa}B sites. In parallel experiments we used the mouse collagen type XI promoter to study cell-type-specific promoter activity in chondrocyte-specific cells (SW1353) and undifferentiated chondroprogenitor cells (ATDC5).

Results. Incorporation of multiple NF-{kappa}B sites into the MMP-9 promoter enhanced activity while maintaining disease specificity. Further, manipulation of the mouse collagen type XI (mColXI) promoter by the incorporation of SOX9 enhancer sites downstream of a reporter gene, increased gene activity while maintaining cell type specificity.

Conclusions. Manipulation of promoter and enhancer regions can improve transcriptionally targeted genes. A combination of these systems, in the context of the canine model, has the potential to improve the safety of osteoarthritis gene therapy vectors.

Keywords: Osteoarthritis; Canine model; Gene therapy; Transcription.
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