Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis
Technical Report,30 Sep 2016,29 Sep 2017
Tel Aviv University Tel Aviv Israel
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During the three year of the award, our major research achievementsfindings were as follows i Farnesylthiosalicylic acid FTS therapy, 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 drug methotrexate MTX provides a superior protective effect compared to monotherapy. iii In the AIA model the FTS derivative, F-FTS, showed higher therapeutic efficacy compared to FTS. iv The functional genomics studies showed that FTS therapy inhibits the in vivo TH17 immune response. v FTS semi-prophylactic therapy in the mouse collagen-induced arthritis CIA model was highly effective and equal to MTX therapy. vi FTS and F-FTS were equally effective therapies in the CIA model and FTS monotherapy was non-inferior to combined FTSMTX therapy. vii The therapeutic effect of FTS treatment in the CIA model was also coupled with attenuation of the in vivo IL-6, IL-17 and IL-22 cytokines Th17 type response to pathogenic autoantigens. 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.
- Medicine and Medical Research