Objective: To examine the safety and tolerability of a single intraarticular injection of rAAV2-TNFR:Fc, an adeno-associated virus serotype 2 vector containing the cDNA for the human tumor necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis.
Methods: In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumor necrosis factor-alpha (TNF-α) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intraarticular injection of rAAV2-TNFR:Fc at 1x1010 (n=5) or 1x1011 (n=6) DNase resistant particles per mL joint volume or placebo (n=4) into a knee (n=14) or ankle (n=1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a 4-point scale, were evaluated.
Results: Intraarticular injections of rAAV2-TNFR:Fc were well-tolerated with no major safety issues. One event, mild knee pruritis, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. Twelve weeks after injection, a 2-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively.
Conclusion: A single dose of intraarticular rAAV2-TNFR:Fc appears to be safe and well-tolerated in subjects without concurrent systemic TNF-α antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.