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Reduction of arthritis following intra-articular administration of an adeno-associated virus serotype 5 expressing a disease-inducible TNF-blocking agent
  1. J Adriaansen1,
  2. M Khoury2,3,
  3. C J de Cortie4,
  4. F J Fallaux4,
  5. P Bigey5,
  6. D Scherman5,
  7. D J Gould6,
  8. Y Chernajovsky6,
  9. F Apparailly2,3,
  10. C Jorgensen2,3,
  11. M J B M Vervoordeldonk1,4,
  12. P P Tak1,4
  1. 1Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  2. 2Inserm, U 475, F-34197 Montpellier, France
  3. 3Université Montpellier1, UFR de Médecine, F-34000 Montpellier, France
  4. 4Arthrogen BV, Amsterdam, the Netherlands
  5. 5Inserm, U 640, F-75006 Paris, France; CNRS, UMR8151, F-75006 Paris, FranceUniversité Paris Descartes, Faculté de Pharmacie, Laboratoire de Pharmacologie Chimique et Génétique, F-75270 Paris, France; and Ecole Nationale Supérieure de Chimie de Paris, F-75005 Paris, France
  6. 6Bone and Joint Research Unit, William Harvey Research Institute, Barts and The London Queen Mary’s School of Medicine and Dentistry, University of London, London, UK
  7. 7Service Clinique d’Immuno-Rhumatologie, CHU Lapeyronie, F-34295 Montpellier, France
  1. Correspondence to:
    Paul P Tak
    MD, PhD, Academic Medical Center, Div. of Clinical Immunology & Rheumatology, Meibergdreef 9, Room F4-218, 1105 AZ Amsterdam, The Netherlands; p.p.tak{at}amc.uva.nl

Abstract

Background: In the context of preclinical development, we studied the potential of intra-articular gene delivery using a recombinant adeno-associated virus 5 (rAAV5) encoding a chimeric human tumour necrosis factorα (TNFα) soluble receptor I linked to a mouse immunoglobulin heavy chain Fc portion (TNF receptor I; TNFRI-Ig).

Methods: Expression was under control of a nuclear factor kappa B (NFκB)-responsive promoter and compared with a cytomegalovirus (CMV) promoter (rAAV5.NFκB-TNFRI-Ig and rAAV5.CMV-TNFRI-Ig, respectively).

Results: Fibroblast-like synoviocytes transduced in vitro with rAAV5.NFκB-TNFRI-Ig were able to produce TNFRI-Ig protein in response to several stimuli, and this was inhibited upon treatment with a specific NFκB blocking agent. A bioassay revealed that the synthesised TNFRI-Ig was bioactive, showing a higher affinity for human than for rat TNFα. Transcription of the transgene and protein production were detectable in joints injected with both constructs. No dissemination of the vector was observed outside the joints. A significant reduction in paw swelling was seen in rats treated with rAAV5.NFκB-TNFRI-Ig. This clinical effect was accompanied by a decrease in pro-inflammatory cytokine levels and an increase in IL10 expression in the synovium.

Conclusion: These results provide evidence that intra-articular gene therapy using rAAV5 encoding TNFRI-Ig may be a safe and feasible approach for the treatment of rheumatoid arthritis. The higher affinity for human TNFα suggests that in patients with rheumatoid arthritis the therapeutic effect might be even more pronounced than in rat adjuvant arthritis.

  • ACR, American College of Rheumatology
  • CMV, cytomegalovirus
  • Ct, threshold cycle (Ct)
  • DMEM, Dulbecco’s modified Eagle’s medium
  • FCS, fetal calf serum
  • FLS, fibroblast-like synoviocyte
  • GADPH, glyceraldehyde phosphodehydrogenase
  • HRP, horseradish peroxidase
  • IL, interleukin
  • LPS, lipopolysaccharide
  • NFκB, nuclear factor kappa B
  • PDTC, pyrrolidinedithiocarbamate
  • rAAV, recombinant adeno-associated virus
  • TNFR, tumour necrosis factor receptor
  • AAV
  • gene therapy
  • TNF receptor I
  • arthritis
  • gene transfer
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Footnotes

  • Published Online First 15 March 2007

  • The first two authors contributed equally to this work.

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