MTHFD1/2 inhibitors as breakthrough therapy in Rheumatoid arthritis

Purpose and goal:

The aim of this study was to uncover the regulatory role of MTHFD1/2 and folate metabolism in rheumatoid arthritis immune responses, potentially leading to advanced treatments utilizing newly synthesized MTHFD1/2 inhibitors and to the identification of novel biomarkers of response to current therapies.

Expected results and effects:

The results of this study provide evidence for the involvement of MTHFD1/2 in rheumatoid arthritis pathogenesis, its role as a biomarker of response to current standard-of-care treatments and the potential for utilizing nanomolar MTHFD1/2 inhibitors as a new therapeutic strategy for rheumatoid arthritis. These findings could pave the way for future clinical trials involving patients with rheumatoid arthritis who are unresponsive to current therapies or have discontinued treatment due to adverse effects.

Approach and implementation:

For this study, we a) analysed publicly available transcriptomic data of large cohorts with patients with rheumatoid arthritis to track MTHFD1/2 expression during disease progression and across different existing treatments , b) used advanced microscopy on patient immune cells to further examine MTHFD1/2 levels, c) conducted ex vivo studies with patient T cells to assess mechanistically the effects of MTHFD1/2i on alleviating the pathogenic cell profile and d) tested the MTHFD1/2i in mice with rheumatoid arthritis to assess treatment efficacy.