Studying the Immunomodulatory Effects of Small Molecule Ras Inhibitors in Animal Models of Rheumatoid Arthritis
Abstract
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 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 FTS+MTX 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2018
- Accession Number
- AD1095073
Entities
People
- Einav Vax
- Galit E. Sfadia
- Itamar Goldstein
- Itzhak B. Moshe
- Ronit Morad Zayoud
- Yoel Kloog
Organizations
- Tel Aviv University