Thioredoxin mimicry: novel treatment of toxicant-mediated inhalational lung injur

硫氧还蛋白拟态：毒物介导的吸入性肺损伤的新治疗方法

• 批准号: 8735374
• 负责人: Garry John Southan
• 金额: $ 77.45万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735374
• 关键词: 3-nitrotyrosine; Acetylcysteine; Acute; Acute Lung Injury; Amides; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Applications Grants; Biological Markers; Blood; Body Weight; Breathing; Canis familiaris; Chlorine; Clinical; Collaborations; Conscious; Cysteine; Cytoprotection; Dependence; Dose; Electrons; Ensure; Enzymes; Epithelial; Euthanasia; Evaluation; Exposure to; Fibrin; Funding; Gases; Gene Expression; Glutathione Disulfide; Guidelines; Health; Histologic; Human; Hydrogen Sulfide; Hydrolysis; Infiltration; Inflammation; Inflammatory; Inhalation Exposure; Injection of therapeutic agent; Injury; Interleukin-10; Investigation; Lipid Peroxidation; Liquid substance; Lung; Malondialdehyde; Mechanics; Mediating; Mitochondria; Modeling; Morphology; Mus; NADP; NQO1 gene; Natural regeneration; Normal saline; Oxidation-Reduction; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phosgene; Placebo Control; Placebos; Plasma; Prodrugs; Proteins; Rattus; Reactive Oxygen Species; Reducing Agents; Research Institute; Resuscitation; Rodent; Safety; Schedule; Secondary to; Series; Shunt Device; Staining method; Stains; Stress; Structure of parenchyma of lung; Sulfhydryl Compounds; Testing; Therapeutic; Thioredoxin; Tight Junctions; Time; Toxicant exposure; Toxicogenetics; Toxicology; Tumor Necrosis Factor-alpha; Work; analog; base; claudin 4; clinically relevant; clinically significant; cysteinylproline; cytochrome c oxidase; design; disulfide bond reduction; dosage; drug development; immunoreactivity; in vivo; indexing; lung injury; male; manufacturing scale-up; mimetics; mimicry; mitochondrial dysfunction; mortality; neutrophil; novel; protein expression; safety study; small molecule; surfactant; thioester; toxicant; wet lung

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.

描述（由申请人提供）：Radikal Therapeutics发明了一种新型的硫氧还蛋白（TRX）模拟物，旨在通过吸入毒性气体（COCL2），氢气（H2S）和氯化（Cllorine（Cllorine）（Cllorine（cl2s））吸入毒性气体（COCL2），触发急性肺损伤（ALI）。 TRX是治疗吸入毒物介导的肺损伤的理想药物靶标，因为它充当了主要的细胞内开关，可调节控制细胞保护，炎症和凋亡的蛋白质的TRX超家族活性。我们的候选分子（R-911）是具有稳定硫醇基团的前药，与血浆接触到其母体形式（功能活性TRX Mimetic（R-952））后立即进行转化。用R-911复苏可深刻地减少受吸入CL2和COCL2或注射H2S供体NASH的小鼠的组织学损伤，炎症和死亡率。 AIM＃1：定义药效学，治疗时间窗口，最佳给药时间表以及R-911的作用机理，在鼠COCL2和H2s的恢复中的动作机理。 BALB/C小鼠将暴露于全身COCL2或H2S 20分钟。 A系列：在吸入后1和7天的安乐死时，将在一系列与临床上相关的损伤指标上对肺组织和支气管肺泡液进行评分：形态，渗出性炎症，氧化还原应激，表面活性剂表达和活性，炎症和抗炎和抗炎的经典型，粘液和粘液式粘膜和粘液化。这些生物标志物将与血浆和肺组织中R-911的浓度及其母体形式的R-952相关，以构建一种可以指导大型动物和临床给药的药效学谱。系列B：最佳的R-911剂量参数（数量，剂量时间表，开始时间）在A系列A中阐明的28天研究将在BALB/C小鼠中使用，其中暴露于COCL2和H2S后跟踪体重和生存。 AIM＃2：在COCL2和H2S吸入暴露的犬模型中，建立R-911作为救援疗法的药效学特征。我们将在有意识的，自发的呼吸犬中建立COCL2和H2的最佳浓度，这些犬能产生可再现且具有临床意义的ALI模型。接下来，我们将在选定的浓度下进行安慰剂对照的疗效研究，并在COCL2和H2S暴露结束后30分钟开始建立IM辅助R-911（安慰剂 + 3剂量水平）的剂量依赖性。 R-911的功效将通过对Ali生物标志物以及肺分流器和力学的影响来确认。 AIM＃3：根据Bioshield指南，建立R-911在毒理学，ADME/PK和安全药理学方面的急性安全性，稳定性和耐受性。我们将扩大和制造GMP级R-911，并进行GLP级ADME/PK，安全药理学，遗传毒理学以及大鼠和狗的体内毒理学研究。完整的IND应用程序将被编译并提交给FDA，以支持疗效和安全研究。