Platform for the Delivery of Unformulated RNA In Vivo

Abstract

The successful delivery of RNA therapeutics is the gating hurdle to greater clinical translation and utility of this novel class of therapeutics. Delivery strategies today are limited and predominantly rely on lipid nanoparticles or conjugates, which can facilitate hepatic delivery but are poor for achieving uptake outside the liver. The ability to deliver RNA to other organs outside the liver in a formulation-agnostic approach could serve to unlock the broader potential of these therapies and enable their use in a broader set of disease. Here we demonstrate this formulation-agnostic delivery of two model siRNAs using low-frequency ultrasound to the gastrointestinal (GI) tract. Unformulated siRNAs targeting β-catenin (Ctnnb 1) and Sjögren syndrome antigen B (SSB) genes were successfully delivered to colonic mucosa in mice, achieving robust knockdown of the target mRNA from whole-colon tissue samples. Indeed, the capacity to target and successfully suppress expression from genes underscores the power of this platform to rapidly deliver unformulated and unoptimized sequences against a range of targets in the GI tract.

Keywords: Antisense therapy; Drug delivery; Inflammatory bowel disease; Mucosal delivery; RNA; Sjögren syndrome Antigen B; Ulcerative colitis; Ultrasound; β-catenin.