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Journal of Virology, April 1999, p. 3410-3417, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Disease-Inducible Transgene Expression from a Recombinant Adeno-Associated Virus Vector in a Rat Arthritis Model

Ru-Yu Pan,1,2,3 Xiao Xiao,4 Show-Li Chen,1 Juan Li,4 Leou-Chyr Lin,3 Hsian-Jenn Wang,5 and Yeou-Ping Tsao1,*

Department of Microbiology and Immunology1 and The Graduate Institute of Medical Science,2 National Defense Medical Center, and Department of Orthopaedics3 and Department of Plastic Surgery,5 Tri-Service General Hospital, Taipei, Taiwan, Republic of China, and Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 152614

Received 1 September 1998/Accepted 12 November 1998

Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting 1% of the world's population, with significant morbidity and mortality. In this study, we investigated a recombinant adeno-associated virus (rAAV) vector for its potential application in RA gene therapy. rAAV encoding Escherichia coli beta -galactosidase was injected into rat joints which had already been induced into acute arthritis after local lipopolysaccharide (LPS) administration, and the efficiency of in vivo transduction was evaluated. We observed a striking correlation between vector transgene expression and disease severity in arthritic joints. The inflammatory reaction peaked at 3 to 7 days after LPS treatment, and, at the same time, 95% of the synoviocytes had high-level transgene expression. Gene expression diminished to the basal level (5%) when the inflammation subsided at 30 days after LPS treatment. More importantly, the diminished transgene expression could be efficiently reactivated by a repeated insult. The transgene expression in normal joints transduced with rAAV remained low for a long period of time (30 days) but could still be induced to high levels (95%) at 3 to 7 days after LPS treatment. This is the first demonstration of disease state-regulated transgene expression. These findings strongly support the feasibility of therapeutic as well as preventative gene transfer approaches for RA with rAAV vectors containing therapeutic genes, which are expected to respond primarily to the disease state of the target tissue.

* Corresponding author. Mailing address: National Defense Medical Center, Department of Microbiology and Immunology, Taipei, Taiwan, ROC. Phone: 886-2-23683465. Fax: 886-2-23686028. E-mail: yptsao{at}mail.ht.net.tw.

Journal of Virology, April 1999, p. 3410-3417, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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