Oral RNA Interference Therapy for Celiac Disease using a Polymeric Microsphere Formulation

Abstract

\n Celiac disease is a chronic inflammatory condition characterized by activation of the immune system in response to deamidation of gluten peptides brought about by tissue transglutaminase-2 (TG2). Overexpression of interleukin-15 (IL-15) in the intestinal epithelium and the lamina propria leads to the dysregulation of the immune system, leading to epithelial damage. The goal of this study was to develop an RNA interference therapeutic strategy for celiac disease using a combination of TG2 and IL-15 gene silencing in the inflamed intestine. TG2 and IL-15 silencing siRNA sequences, along with scrambled control, were encapsulated in Nanoparticle-in-Microsphere Oral System (NiMOS) and administered in poly(I:C) mouse model of celiac disease. Single TG2 and IL-15 siRNA therapy as well the combination showed effective gene silencing in vivo. Additionally, it was found that IL-15 gene silencing alone and combination in NiMOS significantly reduced other proinflammatory cytokines. The tissue histopathology data also confirmed a reduction in immune cell infiltration as well as restoration of the mucosal architecture and barrier function in the intestine upon treatment. Overall, the results of this study show evidence that celiac disease can be potentially treated with an oral microsphere formulation using a combination of TG2 and IL-15 RNA interference therapeutic strategy.