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• W2149750140 abstract "Nuclear factor (NF)-κB is highly activated in the synovium of rheumatoid arthritis (RA) patients, and can induce transcription of many proinflammatory molecules. Phosphorylation of inhibitor of κB (IκB) proteins is an important step in NF-κB activation and under inflammatory conditions is regulated predominantly by IκB kinase (IKK)β. Consequently, specific targeting of IKKβ in the joint, using gene therapy, presents a sophisticated treatment option for arthritis. In the present study we investigated the effect of inhibiting IKKβ in adjuvant arthritis (AA) in rats, using recombinant adeno-associated virus (rAAV)-mediated intraarticular gene therapy. For this purpose rAAV5 carrying the dominant negative IKKβ gene (AAV5.IKKβdn) or control AAV5.eGFP was injected into the right ankle joint. Rats treated with AAV5.IKKβdn in early arthritis exhibited significantly reduced paw swelling (p < 0.05). Immunohistochemical analysis of synovial tissue revealed reduced levels of interleukin (IL)-6 (p = 0.005) and tumor necrosis factor-α (TNF-α) (p = 0.03), whereas IL-10 levels were not affected. No significant effect was found on cartilage and bone destruction, or on matrix metalloproteinase-3 and tissue inhibitor of matrix metalloproteinase-1 expression. Injection of AAV5.IKKβdn in the preclinical phase showed only a marginal effect on arthritis. Importantly, in this study we also demonstrate for the first time that our vector is capable of transducing human RA whole synovial tissue biopsies ex vivo, resulting in reduced IL-6 production after TNF-α stimulation (p = 0.03). In conclusion, we are the first to demonstrate that rAAV5 can be used to successfully deliver a therapeutic gene (IKKβdn) to the synovium, resulting in reduced severity of inflammation in AA in vivo and proinflammatory cytokine production in human RA synovial tissue ex vivo. This translational research represents a crucial next step toward the development of gene therapy for application in humans." @default.
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• W2149750140 date "2006-08-01" @default.
• W2149750140 modified "2023-09-27" @default.
• W2149750140 title "Amelioration of Arthritis by Intraarticular Dominant Negative IKK<i>β</i> Gene Therapy Using Adeno-Associated Virus Type 5" @default.
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• W2149750140 doi "https://doi.org/10.1089/hum.2006.17.821" @default.
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