Targeting NF-kB signaling in macrophages through drug repurposing to treat inflammation

With an aging population, chronic inflammatory disorders like Rheumatoid Arthritis (RA) are causing an increasing burden on society. RA is an autoimmune disease that affects the synovial joints, resulting in the destruction of cartilage and bone, leading to disability and premature death, with 0.5 to 1 % of the population being affected in the United States and northern Europe. A growing body of evidence suggests a critical role of immune cell infiltration in RA pathogenesis in both humans and animal models. With current treatments not affecting disease progression, there are no drugs available to cure RA. The central hypothesis of my PhD thesis is that a combinational approach of studying macrophage cell biology and pursuing drug development will identify pathways that play key roles in chronic inflammatory diseases such as RA, which can be targeted for therapeutic benefit.
So far, traditional de novo drug discovery has fallen short of satisfying this unmet clinical need for better anti-inflammatory drugs. Therefore, we will use drug repurposing as an alternative strategy to identify existing drugs or small molecules with anti-inflammatory properties. Increasing costs of de novo drug discovery combined with long development timelines are major challenges in drug development. Development costs of repurposed drugs are about 10 % of what it costs to market a novel drug and the process is significantly less time consuming than traditional drug development. In addition, the risk of failure is lower for repurposed drugs, as many compounds already have well-defined efficacy and safety profiles. One prominent example for successful drug repurposing is dexamethasone, which was originally used for the treatment of arthritis, asthma and various skin conditions. The steroid was recently found to reduce mortality by up to one-third in patients with severe COVID-19 pneumonia by inhibiting the release of pro-inflammatory cytokines. Here, we will carry out screens of compound libraries to identify compounds that target pro-inflammatory pathways in macrophages linked to chronic inflammatory diseases like RA, resulting in the modulation of cytokine production and inflammasome activation. The aim will be to find new therapeutic options that inhibit inflammation and promote tissue repair, thus offering permanent disease remission.