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 发明了一种新型硫氧还蛋白 (Trx) 模拟物，用于复苏因吸入光气 (COCl2)、硫化氢 (H2S) 和有毒气体而引发的急性肺损伤 (ALI)。氯（Cl2）。 Trx 是治疗吸入性毒物介导的肺损伤的理想药物靶标，因为它充当细胞内主开关，调节控制细胞保护、炎症和细胞凋亡的 Trx 蛋白超家族的活性。我们的候选分子 (R-911) 是一种具有稳定硫醇基团的前药，在与血浆接触后立即转化为其母体形式，即功能活性 Trx 模拟物 (R-952)。使用 R-911 进行复苏可显着降低吸入 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。目标#1：确定 R-911 在小鼠 COCl2 和 H2S 吸入暴露复苏中的药效学、治疗时间窗、最佳给药方案和作用机制。 Balb/c 小鼠将暴露于全身 COCl2 或 H2S 20 分钟。 A系列：吸入暴露后1天和7天安乐死后，将对肺组织和支气管肺泡液进行一系列临床相关损伤指数评分：形态、渗出性炎症、氧化还原应激、表面活性剂表达和活性、促炎和抗炎基因表达、粘膜屏障功能障碍和线粒体完整性。这些生物标志物将与血浆和肺组织中 R-911 及其母体形式 R-952 的浓度相关，以构建指导大型动物和临床剂量的药效学特征。 B 系列：A 系列中阐明的最佳 R-911 给药参数（数量、剂量方案、起始时间）将用于 Balb/c 小鼠的一项为期 28 天的研究，其中跟踪暴露于 COCl2 和硫化氢。目标#2：建立 R-911 作为 COCl2 和 H2S 吸入暴露犬模型救援疗法的药效学特征。我们将在有意识、自主呼吸的犬科动物中建立 COCl2 和 H2S 的最佳浓度，从而产生可重复且具有临床意义的 ALI 模型。接下来，我们将在选定的浓度下进行安慰剂对照功效研究，并确定在 COCl2 和 H2S 暴露结束后 30 分钟开始肌内注射 R-911（安慰剂 + 3 个剂量水平）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和力学的影响来证实。目标#3：根据 BIOSHIELD 指南，在毒理学、ADME/PK 和安全药理学 IND 支持研究中确定 R-911 的急性安全性、稳定性和耐受性。我们将扩大生产GMP级R-911，并开展GLP级ADME/PK、安全药理学、遗传毒理学以及大鼠和犬体内毒理学研究。将编制完整的 IND 申请并提交给 FDA 以支持功效和安全性研究。