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Disease- and cell-type-specific transcriptional targeting of vectors for osteoarthritis gene therapy: further development of a clinical canine model.
- Source :
-
Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2005 Jun; Vol. 44 (6), pp. 735-43. Date of Electronic Publication: 2005 Mar 09. - Publication Year :
- 2005
-
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-1beta and tumour necrosis factor-alpha).<br />Methods: Initial analysis of MMP-9 deletion constructs was made using a luciferase reporter system. The promoter was subsequently engineered to incorporate multiple NF-kappaB 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).<br />Results: Incorporation of multiple NF-kappaB 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.<br />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.
- Subjects :
- Animals
Base Sequence
Cell Line, Tumor
Collagen Type XI genetics
Disease Models, Animal
Dogs
Gene Deletion
Genetic Vectors genetics
High Mobility Group Proteins genetics
Interleukin-1 genetics
Introns genetics
Mice
Mutation genetics
NF-kappa B genetics
Osteoarthritis therapy
Promoter Regions, Genetic genetics
SOX9 Transcription Factor
Transcription Factors genetics
Tumor Necrosis Factor-alpha genetics
Genetic Therapy methods
Matrix Metalloproteinase 9 genetics
Osteoarthritis genetics
Transcription, Genetic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1462-0324
- Volume :
- 44
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Rheumatology (Oxford, England)
- Publication Type :
- Academic Journal
- Accession number :
- 15757961
- Full Text :
- https://doi.org/10.1093/rheumatology/keh590