Targeting DNA Damage Response and Metabolism for Precision Medicine in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease that affects millions of people worldwide, and its negative health burden is accelerating in the ageing population.

Despite many available treatments, up to 40% of RA patients do not respond sufficiently to current therapies and the needs for a precision medicine approach and new treatments are pressing. The complexity of RA and unselective mechanisms of action of existing drugs are challenges. Current treatments also have unintended adverse effects because they affect healthy cell types in the body.

The proposed project DDRAsTic focuses on a particular enzyme called MTHFD2, which plays a crucial role in the metabolism of folate and DNA damage response of activated T cells. Recent research and preliminary data, suggest that MTHFD2 is overactive in RA patients.

DDRAsTic aims to address the hyperactive T-cell responses at the core of RA by targeting MTHFD2 with novel inhibitors that spare essential components, thereby minimizing the risk of toxicity and adverse effects.

In parallel, DDRAsTic seeks to understand the underlying reasons for the limited efficacy of current RA treatments and explore potential biomarkers that can predict how patients will respond to standard therapies, with a specific focus on understanding the involvement of MTHFD2. The aim is to introduce a precision medicine approach in RA and identify a novel treatment.

To achieve this, DDRAsTic adopts a multidisciplinary approach and uses patient-derived specimens, RA animal models and bioinformatics analysis from large cohorts of RA patients to undergo advanced imaging, cellular and molecular techniques.

Overall, these analyses aim to provide insights into MTHFD2's regulatory role in abnormal immune responses and advance RA treatment by introducing precision medicine approaches and overcoming treatment toxicity.