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Multicomponent plasmid protects mice from spontaneous autoimmune diabetes

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posted on 13.08.2021, 15:21 authored by Philippe P. Pagni, Jay Chaplin, Michael Wijaranakula, Johnna D. Wesley, Jaimie Granger, Justen Cracraft, Conor O’Brien, Nikole Perdue, Vijetha Kumar, Shangjin Li, Sowbarnika Sachithanantham Ratliff, Allie Roach, Ayesha Misquith, Chung-leung Chan, Ken Coppieters, Matthias von Herrath
Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).

Funding

The study was funded by Novo Nordisk A/S.

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