Résumé
The TNF-α is one of the most prominent central cytokines in rheumatoid arthritis (RA). We recently demonstrated that systemic non-viral delivery of a siRNA targeting the TNF-α efficiently restore the immunological balance in an experiment model of RA. However, 30% of treated patients do not respond to the anti-TNF-α biotherapies. Strong association of other pro-inflammatory cytokines with the pathogenesis of RA prompted us to determine which one might present therapeutic potential for RNA interference in RA.Two siRNA were designed for each pro-inflammatory cytokine and validated in vitro. The mouse macrophage cell line J774.1 was transfected with siRNAs targeting the mouse IL-1, IL-6, IL-7, IL- 17 or TNF-α. An irrelevant siRNA was used as control. The specificity of cytokine silencing was validated by measuring both mRNA and protein levels following an LPS challenge. Liposomecomplexed siRNAs (10 μg) were injected intravenously in DBA/1 mice, starting at 22 days following arthritis induction. Clinical course of the disease was assessed by paw thickness measuring over time, radiological and histological scores were obtained at euthanasia on day 45. The cytokine profiles were measured by ELISA in sera and knee-joint conditioned media. Complete cure of arthritis was observed when the siRNA targeting the TNF-α was delivered weekly, complexed with the cationic liposome RPR209120/DOPE and a DNA carrier. The therapeutic effect was associated with a decreased secretion of TNF-α in both sera and joints. We are investigating the effect of other pro-inflammatory cytokine silencing in vivo.