Thioredoxin mimicry: novel treatment of toxicant-mediated inhalational lung injur - DESCRIPTION (provided by applicant): Radikal Therapeutics has invented a novel class of thioredoxin (Trx) mimetics intended for the resuscitation of acute lung injury (ALI) triggered by inhalation of the toxic gases phosgene (COCl2), hydrogen sulfide (H2S), and chlorine (Cl2). Trx is an ideal pharmaceutical target for treatment of inhalational toxicant-mediated lung damage because it acts as a master intracellular switch regulating the activity of the Trx superfamily of proteins that govern cytoprotection, inflammation, and apoptosis. Our candidate molecule (R-911) is a prodrug with stabilized thiol groups that undergoes immediate conversion upon contact with plasma to its parent form, the functionally active Trx mimetic (R-952). Resuscitation with R-911 profoundly reduces histologic injury, inflammation, and mortality of mice subjected to inhalation of Cl2 and COCl2 or injection of the H2S donor NaSH. Aim #1: Define the pharmacodynamics, therapeutic time window, optimal schedule of administration, and mechanism of action of R-911 in the resuscitation of murine COCl2 and H2S inhalational exposure. Balb/c mice will be exposed for 20 min to whole-body COCl2 or H2S. Series A: Upon euthanasia at 1 and 7 days post-inhalation exposure, lung tissue and bronchoalveolar fluid will be scored on a battery of clinically-relevant injury indices: morphology, exudative inflammation, redox stress, surfactant expression and activity, pro-inflammatory and anti- inflammatory gene expression, mucosal barrier dysfunction, and mitochondrial integrity. These biomarkers will be correlated with the concentrations of R-911 and its parent form R-952 in plasma and lung tissue in order to construct a pharmacodynamic profile that will guide large animal and clinical dosing. Series B: The optimal R-911 dosing parameters (quantity, dose schedule, time of initiation) elucidated in Series A will be utilized in a 28-day study in Balb/c mice wherein body weight and survival are tracked after exposure to COCl2 and H2S. Aim #2: Establish the pharmacodynamic profile of R-911 as a rescue therapy in canine models of COCl2 and H2S inhalational exposure. We will establish the optimal concentrations of COCl2 and H2S in conscious, spontaneously breathing canines that yield a reproducible and clinically significant model of ALI. We will next conduct placebo-controlled efficacy studies at the selected concentrations, and establish the dose-dependence of IM-administered R-911 (placebo + 3 dose levels) initiated 30 minutes after the end of COCl2 and H2S exposures. Efficacy of R-911 will be confirmed by the impact on ALI biomarkers and pulmonary shunt and mechanics. Aim #3: Establish the acute safety, stability, and tolerance of R-911 in toxicology, ADME/PK, and safety pharmacology IND-enabling studies per BIOSHIELD guidelines. We will scale-up and manufacture GMP-grade R-911 and carry out GLP-grade ADME/PK, safety pharmacology, genetic toxicology, and in vivo toxicology investigations in rats and dogs. A full IND application will be compiled and submitted to the FDA to support efficacy and safety studies.
