743-P: Delayed Diabetes with Proinsulin mRNA Vaccines in NOD Mice

Abstract

Objective: In type 1 diabetes, an immunomodulatory, antigen-specific therapy may abrogate autoimmunity and support immune tolerance to prevent β-cell destruction and disease progression. This study aims to assess the efficacy of a novel proinsulin II mRNA multi-lamellar liposome vaccine in preventing diabetes in the non-obese diabetic (NOD) mouse. We hypothesized that proinsulin mRNA vaccines would restore immunotolerance and delay diabetes. Methods: Proinsulin II was cloned into plasmids for in vitro RNA transcription. mRNA was loaded into DOTAP liposomes. mRNA expression was validated in HEK293 cell line transfection. NOD/ShiLtJ strain mice were obtained at 4 weeks of age. Group 1 received three IV tail vein injections of mRNA vaccines every other day at 8 weeks and one dose at 23 weeks of age. Group 2 remained untreated. Mice were checked weekly for diabetes (glucose ≥250 mg/dl on two measurements one day apart). Kaplan-Meier survival curves, hazard ratio, median time to diabetes, and t-tests were used to compare time to diabetes. Results: The diabetes rate by 32 weeks was 64.2% (9/14) in group 1 compared to 78.6% (11/14) in group 2 (Hazard ratio 1.60 95% CI 0.66-3.86). By 15 weeks, the treatment group had no diabetes compared to 35.7% untreated (p=0.04). Median time to diabetes was 23 weeks in the treatment group and 21 weeks in untreated. Conclusions: Proinsulin II mRNA multi-lamellar liposome vaccines temporarily delay diabetes in NOD mice. Disclosure T.P.Foster: None. M.J.Haller: Board Member; SAB Biotherapeutics, Inc., Consultant; Sanofi, MannKind Corporation. D.Schatz: Advisory Panel; Medtronic, Avotres Inc., QuLab Medical Ltd., Kriya Therapeutics. C.Wasserfall: None. E.Sayour: None. Funding Endocrine Fellows Foundation