RESEARCH - Local delivery of a recombinant adeno-associated vector containing a TNF- antagonist gene in inflammatory arthritis

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Ann Rheum Dis. Published Online First: 4 August 2008.

doi:10.1136/ard.2008.089375

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Extended Report

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, Hobbs 2, Chalmers 3, Hani El-Gabalawy

4, Arthur Bookman 5, Keystone 6, 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

Abstract

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.

http://ard.bmj.com/cgi/content/abstract/ard.2008.089375v1?papetoc

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