Article Text

other Versions

Local delivery of a recombinant adeno-associated vector containing a tumor necrosis factor-α antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study
  1. Philip J Mease (pmease{at}
  1. Seattle Rheumatology Associates/Swedish Medical Center Research, United States
    1. Kathryn Hobbs (khobbs{at}
    1. University of Colorado Health Sciences Center, United States
      1. Andrew Chalmers (achalmers{at}
      1. University of British Columbia, Canada
        1. Hani El-Gabalawy (elgabal{at}
        1. University of Manitoba, Canada
          1. Arthur Bookman (arthur.bookman{at}
          1. University of Toronto, Canada
            1. Edward Keystone (ksnow{at}
            1. University Health Network, Canada
              1. Daniel E Furst (defurst{at}
              1. Geffen School of Medicine at UCLA, United States
                1. Pervin Anklesaria (pervin.anklesaria{at}
                1. Targeted Genetics Corporation, United States
                  1. Alison E Heald (alison.heald{at}
                  1. Targeted Genetics Corporation, United States


                    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.

                    Statistics from

                    Request Permissions

                    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.