Reversal of Hyperglycemia and Suppression of Type 1 Diabetes in the NOD Mouse with Apoptotic DNA Immunotherapy™ (ADi™), ADi-100

Abstract

The antigen-specific apoptotic DNA immunotherapeutic, ADi-100, is designed to suppress type 1 diabetes and consists of two DNA plasmids encoding genetic sequences of the apoptosis-inducing molecule, BAX, and the secreted form of the autoantigen, glutamic acid decarboxylase 65, that is CpG hyper-methylated to avoid inflammatory signaling (msGAD55). Upon a four-day treatment with ADi-100 of young female non-obese diabetic (NOD) mice, the frequency of various tolerogenic dendritic cell populations increased in draining lymph nodes; these cells lost the capacity to stimulate glutamic acid decarboxylase (GAD)-specific CD4+ T lymphocytes and were associated with the previously demonstrated enhancement of GAD-specific regulatory T cells. The efficacy of two ADi-100 formulations containing different proportions of BAX and msGAD55, 1:4 (10/40 µg) and 1:2 (17/33 µg), was evaluated in mildly hyperglycemic pre-diabetic NOD female mice. Both formulations suppressed the incidence of diabetes by 80% in an antigen-specific manner, while all untreated mice developed diabetes. However, treatment of pre-diabetic mice with significantly higher hyperglycemia, denoting progressive disease, showed that ADi-100 1:2 strongly suppressed diabetes incidence by 80% whereas the ADi-100 1:4 was less effective (50%). As an antigen-specific monotherapy, ADi-100 is highly efficacious in reversing elevated hyperglycemia to prevent diabetes, in which increasing apoptosis-inducing BAX content is a promising immune tolerance feature.

Advanced Delivery Strategies for Immunotherapy in Type I Diabetes Mellitus

“…Known diabetic autoantigen-specific epitopes, such as preproinsulin2, GAD65, and ZnT8 as well as epitopes expressing intracellular apoptosis-inducing signalling molecules, such as BAX, have been inserted in pDNA [ 146 - 148 ]. Engineered plasma was designed to induce TDC migration to the draining lymph nodes, which subsequently present antigens to regulate autoantigen-specific Tregs, thus inducing Tregs expansion and suppressing the corresponding Teffs [ 147 ]. Moreover, plasmids can be simultaneously inserted into multiple antigen epitopes to ensure the success of mediating immune tolerance in T1DM.…”

The Role of Gene Therapy in the Treatments of Type 1 Diabetes Mellitus: a review

“…It is therefore unbelievable that RAGE has become a possible therapeutic target for disease treatment and prevention (Le et al, 2020). As an antigen-specific monotherapy, ADi-100 is highly e cacious in reversing elevated hyperglycemia to prevent diabetes, where a promising feature of immune tolerance is the increased apoptosis-inducing BAX content (Alleva et al ,2020). It has been shown that the formulated autoantigenic islet peptides (GAD65206-220, GAD65536-550, Insulin B9-23, and C17-A1) used as a tolerogenic vaccine prevented T1D from developing in prediabetic NOD mice (Zhou et al, 2020).…”