Introduction and Objective: Antigen-specific immune tolerance (ASIT), which suppresses pathogenic immune responses without impairing general immunity, has the potential to transform Type 1 Diabetes (T1D) treatment. We developed NanoGalaxy™, a hydrophilic nanoparticle (HNP) platform for targeted delivery of mRNA to splenic antigen-presenting cells and evaluated its therapeutic potential in the NOD mouse model of T1D and its safety/tolerability in non-human primates. Methods: To assess efficacy in a T1D model, 6- or 15-week-old female NOD mice were injected i.v. twice a week for 3 weeks with HNP encapsulating preproinsulin and GAD65 mRNA (HNP-mRNAIns/GAD) with or without co-encapsulated tolerogenic immune modulators, or vehicle control. Blood glucose levels were monitored weekly through week 30 and immune profiling of splenocytes was performed using flow cytometry and cytokine analyses. To assess tolerability and translatability for priming T cells in a non-human primate model, Cynomolgus macaques received two i.v. doses of HNP encapsulating ovalbumin mRNA (HNP-mRNAOva) administered three weeks apart. T cell responses were assessed by FluoroSpot in PBMC and splenocytes and safety was assessed by analyzing serum biomarkers and CBC. Results: In NOD mice, treatment with HNP-mRNAIns/GAD combined with tolerizing co-payloads reduced diabetes incidence compared to vehicle-treated controls and resulted in an expansion of bulk and antigen-specific regulatory T cells, as well as an increase in exhausted effector T cell populations. In Cynomolgus macaques, immunization with HNP-mRNAOva induced antigen-specific T cell responses and was well tolerated, without evidence of hepatic toxicity or changes in key blood parameters. Conclusion: HNPs are a novel therapeutic platform capable of delivering tolerogenic mRNA-encoded therapies and inducing antigen-specific tolerance in a murine T1D model while demonstrating translational potential and safety in non-human primates. Disclosure J. Lu: None. V. Narayanaswamy: None. K. Lajoie: None. M. Noneman: Employee; Ended; Metagenomi, Inc. Stock/Shareholder; Current; Metagenomi, Inc. J. Popovitz: None. S. Yellai: None. S. Maity: None. G. Tiruchinapally: None. A. Turner: None. S. Wong: None. C.A. Medina: None. K.B. Walsh: Employee; Ended; Genentech, Inc. Employee; Current; GenEdit. H. Zhang: None. D. Newstrom: Employee; Current; Genedit. A. Mandac-Abad: None. Y. Shinn: None. S. Kim: None. T.C. Fong: Consultant; Current; GenEdit, Inc., CitraBio Consulting. Advisory Panel; Current; Orange County Bio, NextNet. D.D. Sloan: None. J.R. Mora: None.
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