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Multicomponent plasmid protects mice from spontaneous autoimmune diabetes

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posted on 13.08.2021, 15:21 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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