Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes

Abstract

Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a lifelong 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 immunomodulatory cytokines (transforming growth factor-β1, interleukin [IL]-10, and IL-2) capable of near-complete prevention of autoimmune diabetes in nonobese 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. In preparation 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 preclinical study demonstrates that this multicomponent, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk for 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 (clinical trial reg. no. NCT04279613, ClinicalTrials.gov).