ABX464 (obefazimod) up-regulates miR-124 to reduce pro-inflammatory markers in inflammatory bowel diseases

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Apolit, Cécile | Campos, Noëlie | Vautrin, Audrey | Begon-Pescia, Christina | Lapasset, Laure | Scherrer, Didier | Gineste, Paul | Ehrlich, Hartmut | Garcel, Aude | Santo, Julien | Tazi, Jamal

Edité par CCSD ; Nature Pub. Group -

International audience. Advanced therapies have transformed the treatment of inflammatory bowel disease; however, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. The first-in-class oral molecule ABX464 (obefazimod), which selectively up-regulates miR-124, has demonstrated its ability to be a well-tolerated treatment with rapid and sustained efficacy in patients with ulcerative colitis (UC). Here, we provide evidence that ABX464 impacts the immune system in vitro , in murine model of IBD, as well as in patients with UC. In vitro , ABX464 treatment up-regulated miR-124 and led to decreases in proinflammatory cytokines including IL17 and IL6, and in the chemokine CCL2. Consistently, miR-124 expression was upregulated in the rectal biopsies and blood samples of UC patients and a parallel reduction in Th17 cells and IL17a levels was observed in serum samples. In a mouse model of induced intestinal inflammation with dextran sulfate sodium, ABX464 reversed the increases in multiple proinflammatory cytokines in the colon and the upregulation of IL17a secretion in the mesenteric lymph nodes. By up-regulating miR-124, ABX464 acts as “a physiological brake” of inflammation which may explain the efficacy of ABX464 with a favorable tolerability and safety profile in UC patients .

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