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Potentialités anti-inflammatoires de l'inhibition génomique et transcriptionnelle du TNF-[alpha] par une approche de type oligonucléotidique

Abstract : Tumor necrosis factor alpha (TNF-[alpha]), a pro-inflammatory cytokine, plays a key role in the pathogenesis of many inflammatory diseases, including arthritis. Neutralization of this cytokine by anti-TNF-[alpha] antibodies has shown its efficacy in rheumatoid arthritis and is now widely used. Nevertheless, some patients currently treated with anti-TNF-[alpha] remain refractory or become non-responder to these treatments. In this context, there is a need for new or complementary therapeutic strategies. Triplex forming oligonucleotides (TFO) can inhibit gene expression with high sequence-specificity by interacting with the DNA double-strand. In this study, we investigated if an anti-TNF-[alpha] TFO had a therapeutic activity on inflammatory processes in vitro and in vivo, as judged from effects on two rat arthritis models. This TFO interacted with the TNF-[alpha] gene promoter, and its inhibitory activity was verified and compared to that of siRNA in vitro. A local intra-articular preventive injection of TFO in both acute and chronic arthritis models significantly reduced the development of the disease. Furthermore, the TFO efficiently blocked synovitis and cartilage and bone destruction in the joints. The results presented here provide the first evidence that gene targeting by anti-TNF-[alpha] TFO modulates arthritis in vivo, thus providing proof of concept that it could be used as therapeutic tool for TNF-[alpha]-dependent chronic inflammatory disorders
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https://hal.univ-lorraine.fr/tel-01746334
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Joseph Paquet. Potentialités anti-inflammatoires de l'inhibition génomique et transcriptionnelle du TNF-[alpha] par une approche de type oligonucléotidique. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2010. Français. ⟨NNT : 2010NAN10067⟩. ⟨tel-01746334⟩

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