Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis
Abstract
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 parameters(Clinical assessment and relevant laboratory/immunological/Molecular 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 FTS/F-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 FTS/F-FTS is inhibition of a pathogenic TH17 autoimmune response to collagen II.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2016
- Accession Number
- AD1034528
Entities
People
- Einav Vax
- Galit E. Sfadia
- Itamar Goldstein
- Itzhak B. Moshe
- Morad Zayoud
- Yoel Kloog
Organizations
- Tel Aviv University