Sustained interleukin-10 transgene expression following intraarticular AAV5-IL-10 administration to horses.

Abstract

Joint trauma leads to posttraumatic inflammation with upregulation of inflammatory cytokines and degradative enzymes. If severe enough, this response can lead to irreversible posttraumatic osteoarthritis (PTOA). Interleukin-10 (IL-10), a cytokine with potent anti-inflammatory effects, has been shown to have chondroprotective effects. A gene therapy approach using a vector to overexpress IL-10 in the joint represents a feasible method of delivering sustained, high doses of IL-10 to posttraumatic joints. We hypothesized that an AAV5 vector overexpressing IL-10 would result in rapid and sustained IL-10 expression following direct intraarticular injection and that this increase would not be reflected in systemic circulation. Additionally, we hypothesized that intraarticular AAV5-IL-10 injection would not induce a local inflammatory response. Twelve horses were assigned to either treatment (AAV5-IL-10-injected) or control (PBS-injected) groups. Middle carpal joints were injected with 1012 vector genomes (vg)/joint or PBS alone (3mL). Serial synovial fluid samples were analyzed for inflammatory changes, IL-10 concentration and vector genome copy number. Serum samples were also analyzed for IL-10 concentration and vector genome copy number. Synovial membrane was collected on day 84. Synovial fluid IL-10 was significantly increased within 48 hours of AAV5-IL-10 injection and remained increased, compared to PBS-injected joints, until day 84. Serum IL-10 was not different between groups. Vector administration did not cause a significant synovial inflammatory response. Vector genomes were detectable in the plasma, synovial fluid and synovial membrane of AAV5-IL-10-injected horses only. IL-10 has the potential to modulate the articular inflammatory response, thereby protecting cartilage from degradation and OA. This study demonstrates the feasibility and efficiency of intraarticular AAV5-IL-10 and future studies investigating the chondroprotective effects of IL-10 in inflamed joints in vivo are warranted.