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THU0076 Adenovirus mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis
  1. C Jorgensen,
  2. F Apparailly,
  3. C Bouquet,
  4. V Millet,
  5. D Noel,
  6. P Yeh,
  7. J Sany
  1. Immuno-Rheumatology, Lapeyronie, Montpellier, France

Abstract

Background Plasmin is essential for metalloproteases (MMP) activation, endothelial cell migration and degradation of the extracellular matrix. The process is common to neoangiogenesis and pannus formation, and 80% of synovial cells express urokinase plasminogen activator receptor (uPAR).

Objectives We inhibited plasmin activation by expressing uPA/uPAR antagonist chimeric molecule (ATF-HSA) through adenoviral mediated gene transfer in experimental arthritis.

Methods Overexpression of ATF-HSA was obtained by IV injection of 109 pfu of a non replicative E1 deleted type 5 adenoviral vector containing murine ATF gene linked to HSA gene under the control of a CMV promoter. Collagen-induced arthritis (CIA) was obtained by immunisation of DBA1 mice with bovine type II collagen in FCA. AdATF-HSA was injected IV on day 25 after immunisation. On day 44, X ray and Immuno-histology of paws were performed. The SCID/hu model was used to assess the effect of adenoviral mediated huATF gene transfer on human rheumatoid synovium angiogenesis.

Conclusion The uPAR antagonist ATF-HSA is a new tool for gene therapy in arthritis. The preventive effect observed may be related to the decrease in angiogenesis rather than inhibition of extracellular matrix degradation.

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