Sepsis is an extreme inflammatory response to an infection that leads to the failure of vital organs. It is a major health problem and the silent killer, responsible for 1 in 5 deaths worldwide. Reversing organ failure, a leading cause of death in sepsis will require specific modulation of biological pathways to prevent disruption of vascular barrier integrity and function, which is currently not possible with the existing drugs available. Employing RNA-based drugs to control protein expression could offer a novel therapeutic strategy in the fight against sepsis. Circular RNAs (circRNAs) are a new class of non-coding RNAs with a unique closed-loop structure that could help address the current limitations of RNA drugs in the disease context and open new therapeutic avenues. Therapeutic delivery of engineered synthetic circRNAs can allow taking full advantage of their unique features and functions, including increased intracellular stability, the ability to affect multiple biological pathways by sponging small RNAs (e.g. microRNA) or proteins, and their potential for cellular context-specific control of protein expression via internal ribosome entry site (IRES)-mediated cap-independent mechanism of protein synthesis. CIRCLE aims to expand the toolbox of therapeutic RNAs by engineering novel synthetic circRNAs for modulation of protein expression in sepsis (WP1 and WP2) and investigate the potential of synthetic circRNA delivery for developing RNA-based pharmacological intervention to reverse sepsis-associated organ failure (WP3 and WP4). By addressing an important gap in the knowledge on the utility of circRNAs for translational research the scientific impact of CIRCLE will extend across the research fields of pharmaceutical sciences, synthetic biology, and medicine.
