ANTI-GLUTEN SYNTHETIC NOTCH RECEPTOR T CELLS FOR THE TREATMENT OF CELIAC DISEASE

Abstract

Celiac disease is a complex autoimmune disorder affecting approximately 0.5-1.7% of the general population. Currently, there are no treatments for Celiac disease aside from a lifelong adherence to a strict gluten-free diet. There is a largely unmet need for alternative treatment options for patients due to the difficulty in maintaining such a diet. Recent advancements in understanding the underlying Celiac disease pathology have identified IL-15 as a key player driving disease morbidity. Synthetic Notch receptors (synNotch) are chimeric Notch receptors in which the extracellular sensing domain and intracellular response domain can be changed to sense and respond to a custom signal. The customizability of these receptors allows for the engineering of cells that can sense a chosen target and induce a chosen response. Here, I propose engineering a synNotch receptor capable of sensing immunogenic gluten peptides and linking its function to the production of the peptide, BNZ-2. BNZ-2 is a γc cytokine receptor antagonist that selectively inhibits IL-15 and IL-21 signaling without impacting IL-2 signaling. I propose engineering T cells to express this synNotch BNZ-2 receptor to disrupt improper IL-15 upregulation driving Celiac disease morbidity.