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

基本信息

批准号：
10282997
负责人：
Jason J Rose
金额：
$ 74.89万
依托单位：
GLOBIN SOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10282997
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 Hour Human Human Engineering Hyperbaric Oxygen Hyperbaric Oxygenation 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 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 hyperbaric chamber 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

项目摘要

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.

项目概要/摘要一氧化碳 (CO) 中毒仍然是死亡和残疾的主要原因，影响着 50,000 人仅在美国一年，就有受害者在暴露于汽车或家用发电机废气后被从火灾中救出或获救。只有两种选择：100% 氧气或通过救护车或医疗后送直升机转移到专门的机构配备紧急高压氧舱的设施由于大约只有300个高压氧舱。对于一氧化碳中毒患者可用的中心，获得和开始治疗的固有延迟极大地限制了事实上，即使采用高压氧治疗，仍有 1-2% 的患者死亡，并且 >25% 的存活患者表现出这种症状。目前尚无针对一氧化碳中毒的即时解毒剂。在目前的提案中，Globin Solutions, Inc.将寻求完成一种新型药物的临床前开发基于使用人血红蛋白的高CO亲和力衍生物的CO中毒的解毒疗法，包括剥离血红蛋白 (S-Hb) 和 NEM 修饰血红蛋白 (NEM-Hb) 资助的正在进行的工作。匹兹堡大学 NIH 证明，亲和力极高的血红素分子可以从红细胞和组织线粒体中封存CO，以逆转CO中毒的全身缺氧。我们发现突变工程人类神经球蛋白 (Ngb) 具有近乎不可逆的共结合亲和力。分子包括四个点突变（Ngb-H64Q-CCC），允许高浓度和静脉注射 Ngb-H64Q-CCC 与 CO 的结合强度比 Ngb-H64Q-CCC 在 CO- 中的结合强度强 500 倍。中毒小鼠体内红细胞清除二氧化碳的时间从 25 分钟增加到 25 秒，结果相反低血压，生存率从不到 10% 提高到 85% 以上，然后通过快速肾脏消除这些发现提供了基于血红素的清除剂分子的概念证明。具有非常高的 CO 结合亲和力，可作为 CO 中毒的潜在解毒剂。人血红蛋白的 CO 亲和衍生物，包括剥离血红蛋白 (S-Hb) 和 NEM 修饰的血红蛋白 (NEM-Hb) 可用于治疗一氧化碳中毒。这些分子可由以下物质产生。在这里，我们建议进行实验来确定 S-Hb 和 S-Hb 的功效和安全性。 NEM-Hb 在我们的小鼠模型中治疗 CO 中毒的效果最好的分子将进一步。发展成为一个完整的 IND 临床前计划：确定小鼠的药代动力学和安全性概况和非人类灵长类动物；经过良好制造程序大规模生产并验证质量； Globin Solutions, Inc. 将利用最近的 A 轮融资来分摊成本。本次拨款中提议的项目费用用于向美国 FDA 提交 IND 申请并首次进行人体试验。总体而言，这些拟议的研究符合 NHLBI 和 NIH 的使命，即高度推进有影响力、重要且新颖的研究，具有改善公众健康的巨大潜力。拟议的研究有可能改变我们目前治疗一氧化碳中毒患者的模式。