Disease-inducible transgene expression from a recombinant adeno-associatedvirus vector in a rat arthritis model

Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting 1% of the world's population, with significant morbidity and mortality. In this s tudy, we investigated a recombinant adeno-associated virus (rAAV) vector fo r its potential application in RA gene therapy. rAAV encoding Escherichia c all beta-galactosidase was injected into rat joints which had already been induced into acute arthritis after local lipopolysaccharide (LPS) administr ation, and the efficiency of in vivo transduction was evaluated. We observe d a striking correlation between vector transgene expression and disease se verity 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 hi gh-level transgene expression. Gene expression diminished to the basal leve l (5%) when the inflammation subsided at 30 days after LPS treatment. More importantly, the diminished transgene expression could be efficiently react ivated by a repeated insult. The transgene expression in normal joints tran sduced with rAAV remained low fur 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 expres sion, These findings strongly support the feasibility of therapeutic as wel l as preventative gene transfer approaches for RA with rAAV vectors contain ing therapeutic genes, which are expected to respond primarily to the disea se state of the target tissue.