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- Title
An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint.
- Authors
van de Loo, F.A.J.; de Hooge, A.S.K.; Smeets, R.L.; Bakker, A.C.; Bennink, M.B.; Arntz, O.J.; Joosten, L.A.B.; van Beuningen, H.M.; van der Kraan, P.K.; Varley, A.W.; van den Berg, W.B.
- Abstract
To achieve a disease-regulated transgene expression for physiologically responsive gene therapy of arthritis, a hybrid promoter was constructed. The human IL-1ß enhancer region (-3690 to -2720) upstream of the human IL-6 promoter region (-163 to +12) was essential in mounting a robust response in HIG-82 synovial fibroblasts and in RAW 264,7 macrophages. A replication-deficient adenovirus was engineered with luciferase (Luc) controlled by the IL-1/IL-6 promoter (Ad5.IL-1/IL-6-Luc). LPS caused a 23- and 4.6-fold induction of Luc. activity in RAW cells infected with Ad5.IL-1/IL-6-Luc or the conventional Ad5.CMV-Luc construct, respectively. Next, adenoviruses (106?ffu) were injected into the knees of C57Bl/6 mice. An intra-articular injection of zymosan, 3 days after Ad5.IL-1/IL-6-Luc, increased Luc. activity by 39-fold but had no effect in the Ad5.CMV-Luc joints. The constitutive CMV promoter was rapidly silenced and could not be reactivated in vivo. In contrast, the IL-1/IL-6 promoter could be reactivated by Streptococcal cell wall (SCW)-induced arthritis up to 21 days after infection. Next the IL-1/IL-6 promoter was compared to the C3-Tat/HIV-LTR two-component system in wild-type, IL-6-/- and IL-1-/- gene knockout mice. Both systems responded well to LPS-, zymosan- and SCW-induced arthritis. However, the basal activity of the IL-1/IL-6 promoter was lower and IL-6 independent. This study showed that the IL-1/IL-6 promoter is feasible to achieve disease-regulated transgene expression for treatment of arthritis.Gene Therapy (2004) 11, 581-590. doi:10.1038/sj.gt.3302182 Published online 19 February 2004
- Subjects
ADENOVIRUSES; DNA viruses; ARTHRITIS; JOINT diseases; TRANSGENES; GENES
- Publication
Gene Therapy, 2004, Vol 11, Issue 7, p581
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3302182