Periodic Reporting for period 1 - CIRCLE (Synthetic Circular RNA therapeutics for prevention of sepsis-associated organ failure)
Período documentado: 2022-07-01 hasta 2024-12-31
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.
CIRCLE addresses major challenges to exploiting synthetic circRNA-therapeutics for modulation of protein expression in the disease setting by focusing on developing novel circRNA tolls with sufficient yield and purity alongside effective methods of circRNA delivery to target cells and tissues. We synthesized unique polymer components allowing us to build nanosized particles suitable for safe and efficient delivery of circRNA and designed novel synthetic circRNAs for improved functionality in the diseased cells. Moreover, CIRCLE strives towards gaining a better understanding of circRNA stability and immunogenicity in the living organism, as well as the efficacy of cap-independent circRNA translation and miRNA/protein sponging mechanisms in the disease environment. Finally, CIRCLE will identify potential patient-relevant targets in diseased cells for developing successful circRNA-based interventions in sepsis.
The ambition of this project is to reshape the future of RNA therapies by understanding and realizing the therapeutic potential of circular RNAs. CIRCLE will help develop new tools and knowledge essential to expand the toolbox of therapeutic RNAs and evaluate circRNA-based intervention for sepsis. We expect that our findings will also have a broader significance in other critically ill patients suffering from diseases with similar pathophysiology to sepsis, including Acute Kidney Injury or Acute Respiratory Distress Syndrome. Given the high-risk/high-gain and multidisciplinary nature of CIRCLE, this project will require the successful integration of multiple research methodologies and disciplines, including drug delivery, chemistry, synthetic biology, biochemistry, and computational biology.