Local delivery of a recombinant adeno-associated vector containing a tumor necrosis factor-
antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study
Philip J Mease 1, Kathryn Hobbs 2, Andrew Chalmers 3, Hani El-Gabalawy 4, Arthur Bookman 5, Edward Keystone 6, Daniel E Furst 7, Pervin Anklesaria 8 and Alison E Heald 8*
1 Seattle Rheumatology Associates/Swedish Medical Center Research, United States
2 University of Colorado Health Sciences Center, United States
3 University of British Columbia, Canada
4 University of Manitoba, Canada
5 University of Toronto, Canada
6 University Health Network, Canada
7 Geffen School of Medicine at UCLA, United States
8 Targeted Genetics Corporation, United States
* To whom correspondence should be addressed. E-mail: alison.heald{at}targen.com.
Accepted 26 July 2008
 | Abstract |
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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-
) 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- 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.
