Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis

During the three year of the award, our major research achievements/findings 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 FTS+MTX 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.