Accession Number:

AD1034528

Title:

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

Descriptive Note:

Technical Report,30 Sep 2015,29 Sep 2016

Corporate Author:

Tel Aviv University Tel Aviv Israel

Report Date:

2016-10-01

Pagination or Media Count:

37.0

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 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.

Subject Categories:

  • Medicine and Medical Research
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE