W153 - Local Delivery of IL-35 mRNA Therapeutic Using Lipid Based Nanoparticles Demonstrates High Preclinical Efficacy to Suppress Acute and Chronic Autoimmune Hepatitis

Abstract Text: IL-35 is an immunosuppressive cytokine inhibiting multiple immune cells. Cytokine clinical use is limited by their short half-live and unwanted toxicity. To overcome these challenges and enable a local delivery at the inflammation site, we have developed an IL35-encoded mRNA therapy vectorized with Lipid-based-nanoparticles (LNP). IL-35 shows promising therapeutic potential for inflammatory diseases due to its pleiotropic immunosuppressive effect as we and others demonstrated by inhibiting activation of T/B, myeloid and fibroblast cells. In addition, IL-35 induces a long-term immunosuppressive loop effect by promoting regulatory B/T cells. Efficacy of our mRNA IL35/LNP strategy was evaluated in acute and chronic hepatitis mouse models. Acute Concavalin A model is characterized by acute inflammation and hepatotoxicity. IL35 mRNA treatment reverses periphery inflammation (pro-inflammatory cytokines: IL-12, IL-6, IFNγ, IL-2) and liver-induced damage associated (transaminase levels) compared to control groups. A local immunosuppressive effect was also observed after treatment with significant inhibition of inflammation and fibrosis associated genes (RNA level). We have confirmed IL35 mRNA therapy efficacy in the CYP2D6 chronic model characterized by autoreactive T/B cells and secretion of anti-CYP2D6 autoantibodies. IL35 mRNA treatment decreases significantly secretion of anti-CYP2D6 autoantibodies compared to control groups. Importantly, total IgG antibodies level was not affected showing the specific effect of IL-35 on activated autoimmune T cells. Altogether, our results illustrate that localized IL-35 expression, through the use of mRNA/LNP therapy, has the potential to reverse acute/chronic hepatitis inflammation and open new perspectives to use this novel mRNA therapeutic strategy for treatment of multiple auto-immune or inflammatory diseases.