Introduction and Objective: Type 1 diabetes (T1D) is characterized by T and B cell responses to pancreatic β islet cell proteins, insulitis, and β islet cell loss. Treatment of NOD mice, at 6 or 10 weeks of age, with poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CNPs) containing recombinant insulin, GAD65, and chromogranin A proteins (CNP-T1D) inhibited antigen (Ag)-specific T cell responses and inhibited T1D progression via regulatory T cell induction. Therefore, we tested the ability of CNP-T1D dosing to reverse dysglycemia. Methods: NOD mice (16 weeks of age) with blood glucose levels between 147-209 mg/dL were randomized into cohorts of 8-10 mice per group. Each dose level was administered as loading dose controls (two doses at 16 and 17 weeks of age) in the absence or presence of booster dosing (three additional doses at 21, 25, and 29 weeks of age). Results: Our data show that by 20 weeks of age, 67% of saline, 45% of CNP-T1D (0.5 mg/dose; loading only), and 60% of CNP-T1D (0.5 mg/dose; loading + booster dosing) treated mice developed T1D, and this increased to 78-100% by 30 weeks of age. In contrast, only 11% of mice in the 2.5 mg CNP-T1D treatment groups developed T1D at 20 weeks of age, and 67% and 89% of these mice remained disease free at 30 weeks of age. Additionally, the 2.5 mg/dose CNP-T1D; loading + booster dosing led to a significant preservation of remission from dysglycemia by 30 weeks of age. Histological analyses confirmed that the 2.5 mg/dose CNP-T1D significantly reduced cell infiltrate into the pancreas leading to preserved islet architecture relative to the Saline group. Conclusion: CNP-T1D was efficacious as assessed by both the prevention of T1D onset and reversal of dysglycemia in a dose-dependent manner. Disclosure D.P. McCarthy: Employee; Current; COUR Pharmaceuticals. M. Chiang: None. A. Elhofy: None. S.D. Miller: Advisory Panel; Current; Cour Pharmaceuticals, NextCure, Inc. J.R. Podojil: None. Funding Studies were funded by COUR Pharmaceuticals
McCarthy et al. (Sat,) studied this question.