Studying the Immunomodulatory Effects of Small Molecule Ras Inhibitors in Animal Models of Rheumatoid Arthritis
Technical Report,30 Sep 2014,29 Sep 2018
Tel Aviv University Tel Aviv Israel
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Our major research achievementsfindings were as follows i Farnesylthiosalicylic acid FTStherapy, a first-in-class oral selective RAS inhibitor, provides a significant immunomodulatory effect in the rat adjuvant-induced arthritis AIA model by all clinical and laboratory outcome parameters. ii Therapy with FTS as an add-on to the methotrexate MTX is more effective compared to monotherapy. iii The FTS derivative, F-FTS, showed higher therapeutic efficacy compared to FTS in AIA. iv The functional genomics studies showed that FTS therapy primarily inhibits the TH17 immune response to pathogenic antigens. v FTS semi-prophylactic therapy in the mouse collagen-induced arthritis CIA model was a highly effective therapy that was noninferior to combined FTSMTX therapy. vi The therapeutic effect of FTS treatment in the CIA model was also coupled with inhibition of the in vivo IL-6, IL-17 and IL-22 Th17 type response to collagen. vii The in vitro studies revealed that FTS is predominantly a potent inhibitor of generation and expansion of TH17 type cells. In conclusion our original findings strongly imply that oral selective RAS inhibitors are potent inhibitors of the TH17-driven autoimmune response in animal models of RA, signifying a strong translational horizon for these compounds.
- Anatomy and Physiology