Hemoglobin-based antidotes for the treatment of carbon monoxide poisoning

用于治疗一氧化碳中毒的血红蛋白解毒剂

• 批准号: 9908358
• 负责人: Jason J Rose
• 金额: $ 25万
• 依托单位: GLOBIN SOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908358
• 关键词: Affect; Affinity; Alkylation; Ambulances; Animals; Antidotes; Binding; Biological Assay; Blood; Blood Chemical Analysis; Blood Pressure Monitors; Brain; Carbon Monoxide; Carbon Monoxide Poisoning; Cardiovascular system; Cause of Death; Cessation of life; Chemistry; Clinical Trials; Complete Blood Count; Cost Sharing; Data; Development; Dose; Drug Kinetics; Emergency Situation; Emergency department visit; Encapsulated; Erythrocytes; Ethylmaleimide; Excision; Exhibits; Exposure to; Fire - disasters; Funding; Generations; Globin; Goals; Grant; Heart; Helicopter; Heme; Hemoglobin; Histopathology; Home environment; Hour; Human; Human Engineering; Hyperbaric Oxygen; Hyperbaric Therapy; Hypotension; Hypoxia; In Vitro; Infusion procedures; Interruption; Intravenous infusion procedures; Kidney; Laboratories; Lead; Lung; Measures; Medical; Mission; Mitochondria; Modeling; Modification; Molecular Conformation; Mus; Mutation; National Heart, Lung, and Blood Institute; Neurocognitive; Neurocognitive Deficit; Output; Oxides; Oxygen; Oxygen Therapy Care; Patients; Persons; Phase; Point Mutation; Poisoning; Procedures; Process; Production; Program Development; Proteins; Provider; Public Health; Renal function; Reproducibility; Safety; Saline; Series; Serum; Small Business Technology Transfer Research; Sodium Chloride; Survivors; Technology; Therapeutic; Time; Tissues; Toxicology; United States; United States National Institutes of Health; Universities; Visit; Work; base; complex IV; cost; cytochrome c oxidase; deoxyhemoglobin; diphosphoglycerate; disability; exhaust; experimental study; first-in-human; immunogenicity; improved; in vivo; lead optimization; liver function; manufacturing process; mitochondrial dysfunction; mortality; mouse model; neuroglobin; nonhuman primate; novel; novel therapeutics; oxidation; oxidative damage; point of care; pre-clinical; preclinical development; programs; research clinical testing; safety assessment

Project Summary/Abstract Carbon monoxide (CO) poisoning remains a major cause of death and disability, affecting 50,000 persons a year in the U.S. alone. Victims removed from fires or rescued after exposure to car or home generator exhaust only have two options: 100% oxygen or transfer via ambulance or medical evacuation helicopter to a specialized facility with emergency hyperbaric oxygen chamber. As there are approximately only 300 hyperbaric oxygen centers available for CO poisoned patients, inherent delays in access to and initiation of therapy greatly limit efficacy. In fact, even with hyberbaric oxygen therapy, 1-2% of patients die and >25% of surviving patients exhibit long-term neurocognitive impairments. There is no point-of-care antidote for CO poisoning currently available. In the present proposal, Globin Solutions, Inc. will seek to complete preclinical development of a novel antidotal therapy for CO poisoning based on the use of high CO affinity derivatives of human hemoglobin, including stripped hemoglobin (S-Hb) and NEM-modified hemoglobin (NEM-Hb). On-going work funded by the NIH at the University of Pittsburgh demonstrates that extremely high affinity heme-based molecules can sequester CO from red blood cells and tissue mitochondria to reverse the systemic hypoxia of CO poisoning. We discovered a near-irreversible CO-binding affinity of mutationally engineered human neuroglobin (Ngb). This molecule includes four point mutations (Ngb-H64Q-CCC) allowing for high concentration and intravenous infusion. Ngb-H64Q-CCC binds CO ≈ 500 times more strongly than Hb. Infusions of Ngb-H64Q-CCC in CO- poisoned mice enhanced CO removal from red blood cells in vivo from 25-minutes to 25-seconds, reversed hypotension, increased survival from less than 10% to over 85%, and were followed by rapid renal elimination of CO-bound Ngb-H64Q-CCC. These findings provide proof of concept, that heme-based scavenger molecules with very high CO binding affinity can be developed as potential antidotes for CO poisoning. In further work, high CO affinity derivatives of human hemoglobin, including stripped hemoglobin (S-Hb) and NEM-modified hemoglobin (NEM-Hb) could be used for the treatment of CO poisoning. These molecules can be produced from expired blood units at a low cost. Here we propose experiments to determine efficacy and safety of S-Hb and NEM-Hb in the treatment of CO poisoning in our mouse models. The best performing molecule will be further developed into a full IND enabling preclinical program: determine pharmacokinetics and safety profiles in mouse and non-human primates; certified Good Manufacturing Procedure production at scale; and validating quality and reproducibility assays. Globin Solutions, Inc. will leverage a recent Series A funding round to cost-share the project expenses proposed in this grant for an IND application to the US FDA and to enable first in human trials. Overall, these proposed studies are in keeping with the mission of the NHLBI and NIH to advance highly impactful, significant, and novel studies that have great potential to improve the public health. Support for these proposed studies has the potential to change our current paradigm for the management of CO poisoning patients.

项目摘要/摘要 一氧化碳（CO）中毒仍然是死亡和残疾的主要原因，影响了50,000人 仅在美国就一年。暴露于汽车或家用发电机排气后，受害者从火中撤离或被救出 只有两个选择：100％氧或通过救护车或医疗疏散直升机转移到专业 带有紧急高压氧室的设施。因为大约只有300个高压氧 可用于中毒患者的中心，继承了治疗的延迟和主动性的限制 效率。实际上，即使接受了氢氧疗法，1-2％的患者和> 25％的生存患者表现出来 长期神经认知障碍。目前没有可用的CO中毒的保健解毒点。 在本提案中，Globin Solutions，Inc。将寻求完成小说的临床前发展 根据使用人血红蛋白的高CO亲和衍生物的使用，用于CO中毒的解毒疗法， 包括剥离的血红蛋白（S-HB）和NEM修饰的血红蛋白（NEM-HB）。由 匹兹堡大学的NIH表明，基于血红素的高亲和力分子可以 从红细胞和组织线粒体中隔离CO，以扭转CO中毒的全身性缺氧。 我们发现了突变工程的人类神经蛋白（NGB）的几乎不可逆转的共同结合性。这 分子包括四个点突变（NGB-H64Q-CCC），允许高浓度和静脉注射 输液。 NGB-H64Q-CCC结合CO≈500倍，比HB高500倍。 NGB-H64Q-CCC的输注 中毒小鼠从体内从25分钟到25秒的体内从红细胞中除去了CO 低血压，生存率从不到10％增加到85％以上，随后是快速肾脏紧急 共同绑定的NGB-H64Q-CCC。这些发现提供了基于血红素的清道夫分子的概念证明 具有很高的CO结合亲和力可以作为CO中毒的潜在解毒剂。在进一步的工作中，高 人血红蛋白的CO亲和力衍生物，包括剥离的血红蛋白（S-HB）和NEM模型 血红蛋白（NEM-HB）可用于治疗CO中毒。这些分子可以用 过期的血液单位以低成本。在这里，我们提出了实验，以确定S-HB的效率和安全性 NEM-HB在我们的小鼠模型中处理CO中毒的治疗。表现最好的分子将进一步 发展成一个完整的IND启用临床前计划：确定鼠标的药代动力学和安全概况 和非人类隐私；经过大规模认证的良好制造程序生产；和验证质量 和可重复性测定。 Globin Solutions，Inc。将利用最近的A系列资金回合来成本共享 该赠款中提出的项目费用向美国FDA提出了IND申请，并首先在人类试验中启用。 总体而言，这些拟议的研究与NHLBI和NIH的使命保持一致 有影响力，重要和新颖的研究，具有改善公共卫生的巨大潜力。支持这些 拟议的研究有可能改变我们当前的CO中毒患者管理范式。