posted on 2021-08-13, 15:21authored byPhilippe 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).