CIRCLE · Synthetic Circular RNA therapeutics for prevention of sepsis-associated organ failure

Reversing organ failure, a leading cause of death in sepsis, requires specific modulation of biological pathways in endothelial cells, 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 the 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 microRNA or proteins, and their potential for cellular context-specific control of protein expression via internal ribosome entry site (IRES)-mediated cap-independent translation.I recently co-developed methods for the circularization and purification of large synthetic circRNAs, and pioneered their use for robust and stable protein expression in eukaryotic cells, to address the short half-life of mRNA in biological systems. I also synthesized a new type of degradable polymers that enable tissue and cell-type selective delivery of large RNAs with low toxicity.Building on those findings, 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 lung and kidney 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.