Antigen-specific tolerogenic mRNA-LNPs for the treatment of autoimmunity 4721

Abstract Description Identifying novel approaches for the treatment of autoimmune disease is of great clinical importance. In particular, there is a great unmet need to identify treatments which suppress symptoms of disease but show reduced off-target side effects compared with general immunosuppressive methods. Here, we demonstrate a novel approach for antigen-specific immune tolerance through the generation of dual-encoding tolerogenic mRNA-lipid nanoparticles (mRNA-LNPs). Specifically, we show that mRNA-LNPs encoding an immunomodulator in combination with disease-specific autoantigens are taken up by DCs and induce an antigen-specific tolerogenic phenotype. Treatment with these tolerogenic dual-target mRNA-LNPs completely prevents the onset of experimental autoimmune encephalomyelitis (EAE) and reverses symptoms in mice with ongoing disease, showing significant improvement over mRNA-LNPs encoding for autoantigens alone. We found that this disease suppression was associated with an increase in antigen-specific FoxP3+ and IL10+ regulatory T cells and a reduction in CNS-infiltrating effector T cells. Finally, we show that mRNA-LNPs can be easily modified to encode a variety of immunomodulators or disease-specific antigens, making this approach an ideal modular platform for the treatment of multiple autoimmune disease. Thus, our results suggest that tolerogenic antigen-specific dual-targeting mRNA-LNPs represent a novel therapeutic platform for the treatment of autoimmune diseases. Funding Sources Supported by Immunocodex. Topic Categories Therapeutic Approaches to Autoimmunity (THER)