Nuclear factor (
NF)-kappaB is highly activated in the synovium of
rheumatoid arthritis (RA) patients, and can induce transcription of many proinflammatory molecules. Phosphorylation of inhibitor of kappaB (IkappaB)
proteins is an important step in
NF-kappaB activation and under inflammatory conditions is regulated predominantly by
IkappaB kinase (
IKK)beta. Consequently, specific targeting of
IKK beta in the joint, using gene therapy, presents a sophisticated treatment option for
arthritis. In the present study we investigated the effect of inhibiting
IKK beta in
adjuvant arthritis (AA) in rats, using recombinant adeno-associated virus (rAAV)-mediated intraarticular gene therapy. For this purpose rAAV5 carrying the dominant negative
IKK beta gene (AAV5.
IKK beta dn) or control AAV5.eGFP was injected into the right ankle joint. Rats treated with AAV5.
IKK beta dn 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-alpha (
TNF-alpha) (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.
IKK beta dn 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-alpha stimulation (p = 0.03). In conclusion, we are the first to demonstrate that rAAV5 can be used to successfully deliver a therapeutic gene (
IKK beta dn) 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.