Targeting Janus kinases in the treatment of autoimmune disease

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

Cytokines comprise a large family of secreted proteins that regulate cell growth and differentiation of many types of cells. These factors are especially important in regulating immune and inflammatory responses, and regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of many autoimmune diseases such as rheumatoid arthritis, SLE, IBD and psoriasis, as well as viral cytokine storm dramatically revealed in COVID-19. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets. We discovered human Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have received two patents related to targeting Jak3 as the basis for a new class of immunomodulatory drugs and established a Cooperative Research and Development Agreement (CRADA) with Pfizer to generate a series Jak antagonists. One compound, tofacitinib, was developed by Pfizer and found to be effective in preclinical models. Tofacitinib and other JAK inhibitors (jakinibs, including abrocitinib and ritlicitinib) are approved for rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, atopic dermatitis, vitiligo, alopecia areata, psoriasis, Crohn disease, ulcerative colitis and COVID-19. Based on preclinical models, we considered that SLE might be an appropriate candidate for this class of drugs and performed a study in the NIH Clinical Center. We found that tofacitinib resulted in significant improvements in cardiometabolic and immunologic disease parameters associated with accelerated atherosclerosis in SLE, with response being associated with the presence of the STAT4 risk allele. Baricitinib has also been studied for dermatomyositis in the Clinical Center and other trials are being developed. This year we have identified patients with STAT4 and STAT6 gain-of-function variants who have been successfully treated with JAK inhibitors. We have also identified patients with SOCS1 loss of function mutations who are also being treated with JAK inhibitors. We have also developed a STAT1 GOF mouse and are using JAK inhibitors in this model to understand how to best utilize these drugs in the setting of interferonopathy.