In the context of preclinical development we studied the potential of intra-articular gene delivery using a recombinant adeno-associated virus 5 (rAAV5) encoding a chimeric human tumor necrosis factor-alpha (TNF-alpha) soluble receptor I linked to a mouse immunoglobulin heavy chain Fc portion (TNFRI-Ig) under control of a nuclear factor (NF)-kB-responsive promoter compared to a CMV-promoter (rAAV5.NF-kB-TNFRI-Ig and rAAV5.CMV-TNFRI- Ig, respectively).
Fibroblast-like synoviocytes (FLS) transduced in vitro with rAAV5.NF-kB-TNFRI-Ig were able to produce TNFRI-Ig protein in response to several stimuli and this was inhibited upon treatment with a specific NF-kB blocking agent. A bioassay revealed that the synthesized TNFRI-Ig was bioactive, showing higher affinity for human than for rat TNF-alpha. Transcription of the transgene and protein production were detectable in joints injected with either construct. Only minimal dissemination of the vector was observed outside the joints. Significant reduction in paw swelling was seen in rats treated with rAAV5.NF-kB-TNFRI-Ig. This clinical effect was accompanied by a decrease in pro-inflammatory cytokine levels and an increase in IL-10 expression in the synovium.
These results provide evidence that intra-articular gene therapy using rAAV5 encoding TNFRI-Ig may be a safe and feasible approach for the treatment of RA. The higher affinity for human TNF-alpha suggests that in RA patients the therapeutic effect might be even more pronounced than in rat adjuvant arthritis.
- TNF receptor
- gene therapy
- gene transfer
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