A novel hydrophilic nanoparticle mRNA-based platform to deliver antigen-specific immune therapies in autoimmune diseases 2334959

Abstract Introduction We developed NanoGalaxy™ a hydrophilic nanoparticle (HNP) platform, to deliver mRNA to spleen antigen-presenting cells (APC) and induce antigen-specific immune tolerance (ASIT) in autoimmune diseases. Methods mRNA delivery to spleen APC and T cell activation were assessed by intravenous (i.v.) injection of HNPs encapsulating GFP and Ovalbumin (Ova) mRNA and flow cytometry. ASIT was assessed in a delayed-type hypersensitivity (DTH) model induced with Ova protein immunization and in the experimental autoimmune encephalomyelitis (EAE) induced with myelin oligodendrocyte glycoprotein peptide (MOGp) immunization. For ASIT therapies, mice were injected i.v. with HNP encapsulating Ova or MOGp mRNAs plus/minus tolerogenic immune modulators. Therapeutic responses were assessed by measuring footpad inflammation (DTH) or clinical scores (EAE), and immune correlates were assessed by cytometric bead array (CBA) and flow cytometry in splenocytes. To assess translatability, Cynomolgus macaques received two i.v. doses of HNPs encapsulating Ova mRNA administered three weeks apart. T cell responses were assessed by FluoroSpot and safety was assessed by analyzing blood parameters. Results In mice, HNPs transfected APCs in spleen with minimal hepatic uptake, and induced antigen-specific T cell responses. HNPs encapsulating Ova or MOGp mRNAs plus tolerogenic immune modulators efficiently induced ASIT in the DTH and EAE models, respectively, while HNPs without tolerogenic co-payloads did not lead to optimal immune tolerance. In Cynomolgus macaques, immunization with HNPs delivering Ova mRNA was well tolerated and induced antigen-specific T cell responses, without evidence of hepatic toxicity or changes in key blood parameters. Conclusion Thus, NanoGalaxy™ HNP is a versatile platform to deliver mRNA-encoded antigens plus immune modulators to spleen APCs and induce ASIT in autoimmune diseases, while showing translational potential and safety in non-human primates. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)