Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis
Technical Report,30 Sep 2015,29 Sep 2016
Tel Aviv University Tel Aviv Israel
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During the first two year of the award, we made several high impact key observations I Prophylactic treatment with Farnesylthiosalicylic acid FTS, a first-in-class oral selective RAS inhibitor, provides a significant immunomodulatory effect in the rat adjuvant-induced arthritis AIA model by all outcome parametersClinical assessment and relevant laboratoryimmunologicalMolecular analyses. II Prophylactic dosing of FTS combined with methotrexate MTX provides a synergistic protective effect 90 disease inhibition. III The FTS derivative, F-FTS, showed superior therapeutic clinical efficacy compared to FTS in the AIA model. IV The detailed bioinformatics analysis of the transcriptomes of relevant splenic CD4 T cells show that FTSF-FTS are potent suppressors of the in vivo induction of a TH17 immune response. V FTS had a non-inferior therapeutic effect as compared to MTX in the collagen type-II induced arthritis CIA mouse model. VI FTS semi-prophylactic treatment alone or combined with MTX was coupled with significant positive attenuation of multiple relevant immunological and laboratory markers -- all strongly implying that the main biological effect of FTSF-FTS is inhibition of a pathogenic TH17 autoimmune response to collagen II.
- Medicine and Medical Research