DYRK1A inhibitors, GLP1 Receptor Agonists and Immunomodulation for Beta Cell Regeneration Therapy in Type 1 Diabetes - Summary Type 1 diabetes (T1D) affects ~2 million people in the US, including children. T1D is a major burden to society in terms of health costs, loss of productivity; it reduces quality of life and expectancy and causes loss of life due to acute and chronic complications. Its incidence is rising worldwide. T1D is mediated by an autoimmune process that destroys insulin-secreting pancreatic beta cells, leading to lifelong insulin-deficiency and hyperglycemia. No cure or fully effective prevention is available, but the key requirements for diabetes reversal are apparent: (1) preservation of residual beta cell mass; (2) promotion of beta cell regeneration; and (3) induction of immune tolerance. The discovery that inhibitors of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) enhance human β-cell regeneration empowers exploring regimens that simultaneously address autoimmunity, β-cell dysfunction and, for the first time, β-cell loss. We will advance this concept in nonobese diabetic (NOD) mice and immunodeficient mouse models, supported by preliminary data showing that: 1) DYRK1A inhibitors together with the GLP-1 receptor agonist (GLP1RA) exenatide synergistically increase human β-cell proliferation and expand β-cell mass in vivo in human islet grafts transplanted into immunodeficient mice; 2) this combination affords protection from cytokine-induced human β-cell death and decreases immunogenicity in vitro; and 3), it rapidly reverses diabetes in newly diagnosed NOD mice pre-treated with anti- CD3 antibody. However, efficacy of short course immune therapies wanes over time and there is a need for safe, chronic treatments that promote immune regulation without inducing immunosuppression. A promising agent is IL-2: at low dose, it selectively promotes regulatory T cells (Tregs) and was safe and effective in treating autoimmunity in experimental models and in clinical trials for several immune-mediated disorders. Our central hypothesis is that DYRK1A inhibition with GLP1R activation in combination with effective, long-term immunomodulation induces stable T1D remission in NOD mice. We propose that this therapy improves β- cell health and number, decreases immunogenicity, and is synergistic with immunomodulation that includes low dose IL-2 therapy to stimulate Treg cells. Specific Aim 1 will advance an expanded combination therapy with immunomodulators (anti-CD3 and IL-2/CD25 fusion protein), a novel and safer DYRK1A inhibitor, and clinically used GLP1Ras, for T1D reversal. Specific Aim 2 will establish the immunological basis by which Treg-targeting by low dose IL-2/CD25 together with immune modulation by anti-CD3 and β-cell enhancement by DYRK1A inhibition/GLP1R activation leads to T1D reversal. Specific Aim 3 will determine the mechanisms impacted by this combination therapy on the human β-cell and human immune cells. This highly translational work will characterize the therapeutic potential of the combination of DYRK1A inhibitors, GLP1RAs and immunomodulators to induce T1D remission, and the cellular/molecular mechanisms involved in the beneficial effects of this treatment, with relevance to both recent onset and established T1D.
