Objective
NF-κB is highly activated in synovium of RA patients, and can induce transcription of proinflammatory cytokines, adhesion molecules, and inducible nitric oxide, among others. Phosphorylation of the inhibitor of κB (IκB) proteins is an important step in NF-κB/Rel activation and is regulated by IκB kinase (IKK). The IKK complex consists of at least three subunits, including IKKα and IKKβ (also called IKK1 and IKK2) and the regulatory subunit IKKγ. In an initial study in Lewis rats with adjuvant arthritis (AA) adenoviral dominant-negative IKK2 (Ad.IKK2dn) significantly ameliorated the severity of disease as evidenced by decreased paw swelling compared with Ad.GFP-treated rats [1]. However, adenoviral vectors are known to be very immunogenic, compromising stable long-term expression of the transgene. Adeno-associated virus (AAV) is considered the most promising vector for gene therapy in RA. In a comparative serotype study we found that direct injection of AAV5 into the ankle joints of rats with AA resulted in the highest synovial transduction, with good expression of the transgene at the protein level until the end of the study, followed by AAV2. In the present study we investigated the effect of inhibiting NF-κB in AA in rats using AAV-mediated intra-articular gene therapy. For this purpose we used the following vectors: AAV5 containing the IKK2dn gene (AAV5.IKK2dn) or AAV2 containing the IκBα-supressor gene (AAV2.IκBα SR).