Tetracycline-Inducible Interleukin-10 Gene Transfer Mediated by an Adeno-Associated Virus: Application to Experimental Arthritis

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Abstract
The adeno-associated viruses (AAV) offer new perspectives for cytokine gene transfer in rheumatoid arthritis (RA) because they are nonpathogenic and allow long-term transgene expression in vivo. Moreover, the use of a tetracycline-inducible promoter allows regulation of therapeutic gene expression. This study assessed the potential long-term gene regulation of a recombinant AAV vector expressing viral interleukin-10 (vIL-10) in human rheumatoid synovium and the therapeutic efficiency in a mouse model of RA. We constructed a recombinant AAV vector in which the transcription of vIL-10 cDNA is controlled by the TetON system. Transduction of human primary RA synovial cells with AAV-tetON-vIL10 conferred in vitro controlled vIL-10 expression. After intramuscular injection, both incidence and severity of collagen-induced arthritis were significantly reduced at macroscopic, radiological, and histological levels in the group of DBA1 mice treated with AAV-TetON-vIL10 vector plus doxycycline after immunization and boosting compared to control groups. When coinjecting two separate AAV vectors, one encoding the inducible vIL-10 and the other the transcriptional activator, a 10 times excess of the transactivator vector dose allowed efficient control of vIL-10 secretion by doxycycline administration or withdrawal, over an 8-week period. Our results supported, for the first time, the utility of AAV-tetON-vIL10 as a therapeutic tool for gene therapy in RA.