Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, which annually affects over thirty million people of all ages worldwide. In developed countries one in five patients diagnosed with sepsis and one in three suffering from septic shock succumb to the disease. To date, therapeutic options for this condition are limited due to complex and systemic nature of the disease and the lack of effective pharmacological interventions. Current therapy consists of antibiotics, fluid resuscitation and supportive care with organ support. The aim of this proposal is to develop an effective pharmacological intervention for treatment of sepsis and sepsis induced multiple organ dysfunction syndrome (MODS) based on the delivery of therapeutic RNAs including short interfering RNA (siRNA) and messenger RNA (mRNA). RNA-based therapeutics grant an unprecedented specificity and control over protein expression. They have also shown tremendous potential to treat various diseases and have demonstrated efficacy and safety in clinical trials. My proposed work will develop novel polymeric nanoparticles to deliver RNA to lungs and kidneys, two major organs at risk of failure during sepsis. There is a clinical evidence supporting the important role of inflammation driven endothelial damage and exacerbation of the immune response in sepsis-induced organ failure thus we will investigate approaches targeting both major inflammatory (NFκB, p38 MAPK) and immunomodulatory (IL-10, IL-7, PD-1/PD-L1) pathways in the endothelial cells and/or infiltrating immune cells. Moreover, we will utilize post-mortem organ biopsies from septic patients to guide the choice of therapeutic targets, which will be further validated in animal models of sepsis. To date, sepsis has acquired the reputation of the “Bermuda triangle” of drug discovery, my cross-disciplinary proposal will develop novel drug delivery technology and actionable knowledge to facilitate proof of concept for an RNA-based intervention for treatment of sepsis and septic shock.
