Bifunctional Modulation of Redox Imbalance for Treatment of Septic Shock

DESCRIPTION (provided by applicant): Sepsis accounts for gt 500K hospitalizations in the USA yearly, of which half will progress to a fatal outcome. Because there are no approved pharmaceutical agents that profoundly improve outcome, the mainstay of care is supportive administration of fluids, oxygen, mechanical ventilation, and antibiotics. Sepsis is driven by widespread tissue injury mediated by alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion. The imbalance of thesetwo free radical species produces major changes in the distribution of extracellular water, disrupts epithelial and endothelial tight junctions, impairs endothelial function and vascular smooth muscle tone, chokes off microcirculatory blood flow, triggerspulmonary arterial hypertension, and raises endothelial permeability. Despite aggressive support, sepsis may progress to a state of circulatory collapse, with widespread tissue dysfunction and multiple organ failure prior to death. A successful treatment of sepsis requires the simultaneous replenishment of nitric oxide and removal of superoxide. To address this unmet clinical need, Radikal Therapeutics is developing R-100, a novel agent formed from the covalent linkage of two redox-based moieties: 1) an organic nitrovasodilator that releases nitric oxide, and 2) a pyrrolidine nitroxide that acts as a superoxide dismutase mimetic, a catalase mimic, and a peroxynitrite decomposition catalyst. In combination, these functionalities allow R-100 to remove toxic reactive oxygen species and deliver nitric oxide without the confounding effect of producing peroxynitrite. In a lethal murine model of endotoxinemia, R-100 treatment prevented signs and symptoms of sepsis and produced 100% survival, vs. 0% survival in controls. We now propose to extend these observations and validate the efficacy of R-100 in a gold-standard ovine model of trauma-associated septic shock. Specific Aim: Establish the efficacy of R-100 in an ovine model of trauma-associated sepsis. We will carryout a placebo-controlled ovine study in which respiratory insufficiency and septic shock are induced in anesthetized, mechanically-ventilated Merino sheep via acute smoke inhalation injury and Pseudomonas aeruginosa pneumonia. Treatment with R-100 will beinitiated 1 hour after trauma and continued for 24 hours. R-100 is expected to 1) block lung inflammation and injury, by reducing wet/dry ratio, lymphatic drainage, lipid peroxidation, neutrophil infiltration, peroxynitrite production, and poly (ADP-ribose) formation, and 2) improve hemodynamics and airway pressures, by reducing pulmonary vascular resistance, peak inspiratory pressure, and pulmonary shunt. These experimental treatment effects are expected to translate in the clinical setting into shorter duration of mechanical ventilation, accelerated discharge from the intensive care unit, and reduced all-cause 30 day mortality. PUBLIC HEALTH RELEVANCE: Sepsis is a leading cause of mortality in the intensive care unit and a major unmet medical need.The sole approved therapy for septic shock is of limited benefit and rarely prescribed. We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically-relevant large animal model.