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document
Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis : a phase 1 dose-escalation safety and tolerability study . OBJECTIVE To examine the safety and tolerability of a single intra-articular injection of rAAV2-TNFR : Fc , an adenoassociated virus serotype 2 vector containing the cDNA for the human tumour 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 tumour necrosis factor alpha ( TNFalpha ) inhibitors with persistent moderate ( grade 2 ) or severe ( grade 3 ) swelling in a target joint due to inflammatory arthritis received a single intra-articular injection of rAAV2-TNFR : Fc at 1 x 10 ( 10 ) ( n = 5 ) or 1 x 10 ( 11 ) ( 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 four-point scale , were evaluated . RESULTS Intra-articular injections of rAAV2-TNFR : Fc were well tolerated with no major safety issues . One event , mild knee pruritus , was considered probably related . Synovial fluid TNFR : Fc protein was not detected ( nor expected ) at the doses used . At 12 weeks after injection , a two-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 intra-articular rAAV2-TNFR : Fc appears to be safe and well tolerated in subjects without concurrent systemic TNFalpha 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 .
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Intervention_Pharmacological
recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene
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Intervention_Pharmacological
rAAV2-TNFR : Fc , an adenoassociated virus serotype 2 vector containing the cDNA
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Intervention_Control
placebo-controlled
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Intervention_Pharmacological
rAAV2-TNFR : Fc
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Intervention_Control
or placebo
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Outcome_Other
safety and tolerability
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Outcome_Other
safety and tolerability
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Outcome_Other
Safety
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Outcome_Physical
changes in injected joint tenderness and swelling scores
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Outcome_Physical
Synovial fluid TNFR : Fc protein
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Outcome_Physical
decrease in swelling
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Outcome_Other
safety and efficacy