Polynitroxylated Pegylated Hemoglobin for Traumatic Brian Injury Resuscitation

聚硝酰化聚乙二醇化血红蛋白用于创伤性布莱恩损伤复苏

基本信息

批准号：
8057277
负责人：
Carleton Hsia
金额：
$ 30万
依托单位：
SYNZYME TECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8057277
关键词：
Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Attention Biological Brain Brain Edema Cattle Cells Cessation of life Chemicals Chemistry Collaborations Colloids Controlled Study Data Dose Dose-Limiting Drug Kinetics Engineering Funding Goals Grant Hemoglobin Hemorrhagic Shock Hospitals Hypotension Immunology In Vitro Injury Intracranial Pressure Lead Ligands Link Military Personnel Modeling Morbidity - disease rate Mus Neurons No-Observed-Adverse-Effect Level Non-Rodent Model Outcome Oxygen Patients Pharmacologic Substance Pharmacology Phase Pilot Projects Preparation Production Property Proteins Protocols documentation Quality Control Rattus Reactive Oxygen Species Research Resuscitation Rodent Rodent Model Safety Screening procedure Solutions Staging Technology Test Result Testing Therapeutic Toxic effect Toxicology Traumatic Brain Injury base brain tissue clinical toxicology clinically relevant cost functional outcomes hemodynamics immunogenicity improved in vivo injured meetings mortality neurotoxic neurotoxicity novel strategies pre-clinical programs safety testing scale up standard of care success

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of morbidity and mortality especially when complicated by secondary insults such as hypotension. Vulnerability of TBI patients to hypotension is well recognized and identifies a key need for new approaches. The goal of this proposal is to develop to IND a neuroprotective, hyper-colloid, oxygen therapeutic, polynitroxylated pegylated hemoglobin (PNPH), for pre-hospital resuscitation in the setting of TBI complicated by hypotension. In a 4-year collaboration between Safar Center for Resuscitation Research and SynZyme Technologies funded by the US Army, previous screening of several solutions based on the strategy of using proteins with covalently linked antioxidant nitroxide moieties produced preliminary data suggesting exciting potential for one such agent, PNPH. PNPH has three components contributing to its unique therapeutic activities: 1) hemoglobin as the protein center provides oxygen delivery capabilities 2) the pegylation moieties of PNPH provide hyper-colloid properties important to stabilizing hemodynamics during hypotension, and 3) the nitroxide moieties of PNPH not only improve the safety of cell-free hemoglobin but also provide anti-oxidant/anti-inflammatory and neuroprotective activities. For decades, attention has focused solely on hemoglobin's ability to carry oxygen. In the case of TBI, it is essential that the treatment not only delivers oxygen but also protects neurons. Polynitroxylation converts pro-oxidant hemoglobin into a neuron-protective oxygen carrier, which is an ideal candidate for the proposed therapy. Preliminary studies of PNPH, prepared by polynitroxylation of carboxy (CO) bovine pegylated hemoglobin are presented. In vitro studies suggest that PNPH is a unique hemoglobin with neuroprotective rather than neurotoxic properties. Similarly, in vivo studies show that this PNPH functioned as a small volume resuscitation solution that maximized hemodynamic stability, survival and brain tissue oxygen levels while minimizing neuronal death, after TBI plus HS in mice and outperformed the current standard of care for civilian and military pre-hospital TBI resuscitation. In the phase I of this translational program, quality controlled PNPH will be evaluated to determine product specifications, efficacy in functional outcome and preliminary toxicology. This will set the stage for a pre-IND meeting to obtain FDA guidance. In phase II, production will be scaled up and requisite CMC and FDA required GLP toxicology and safety testing will be performed in preparation for IND submission at the end of the grant period. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in both civilian and military settings. Secondary insults, such as polytrauma with hemorrhagic shock (HS) are common, especially in cases of severe TBI, and have a devastating impact on outcome. Vulnerability of brain-injured patients to hypotension and brain edema with the current standard of care is well recognized and identifies a key need for new approaches. This application proposes to bring to IND a therapeutic, polynitroxylated pegylated hemoglobin (PNPH), which has been shown to be a unique neuroprotective hemoglobin that functioned as a small volume resuscitation solution that maximized hemodynamic stability, survival and brain tissue oxygen levels while minimizing neuronal death, after TBI plus HS in mice and outperformed the current standard of care for civilian and military pre-hospital TBI resuscitation.

描述（由申请人提供）：创伤性脑损伤（TBI）是发病率和死亡率的主要原因，尤其是在诸如低血压之类的继发性侮辱时复杂化时。 TBI患者对低血压的脆弱性已得到充分认识，并确定了对新方法的关键需求。该提案的目的是发展为神经保护性，超胶体，氧治疗，多硝基氧基化的卵脂化血红蛋白（PNPH），以在降低症中复杂化的TBI中进行院前复苏。在美国陆军资助的Safar复苏研究中心与Synzyme Technologies之间的为期4年的合作中，先前筛选了几种解决方案，基于将蛋白质与共价连接的抗氧化硝基氧化物部分进行的策略，生成了初步数据，提示了一种激动人心的潜力，这是一种此类剂，PNPH，PNPH。 PNPH has three components contributing to its unique therapeutic activities: 1) hemoglobin as the protein center provides oxygen delivery capabilities 2) the pegylation moieties of PNPH provide hyper-colloid properties important to stabilizing hemodynamics during hypotension, and 3) the nitroxide moieties of PNPH not only improve the safety of cell-free hemoglobin but also provide抗氧化剂/抗炎和神经保护活性。几十年来，注意力一直集中在血红蛋白携带氧气的能力上。就TBI而言，必须不仅可以提供氧气，还可以保护神经元。多硝基化将促氧化血红蛋白转化为神经元保护氧载体，这是拟议治疗的理想候选者。提出了通过羧基（CO）牛卵痛化血红蛋白制备的PNPH的初步研究。体外研究表明，PNPH是具有神经保护性而非神经毒性特性的独特血红蛋白。同样，体内研究表明，该PNPH充当了小体积复苏溶液，在小鼠中TBI加HS之后，在最小化神经元死亡的同时最大程度地提高了血液动力学稳定性，存活率和脑组织氧气水平，并且在小鼠中的HS之后，并超过了目前对平民和军事前主源前TBI的护理标准。在该翻译计划的第一阶段，将评估质量控制的PNPH，以确定产品规格，功能结果的功效和初步毒理学。这将为获得FDA指导的预定会议奠定基础。在第二阶段中，将扩大生产规模，必要的CMC和FDA所需的GLP毒理学和安全测试，以准备在赠款期结束时进行IND提交。公共卫生相关性：创伤性脑损伤（TBI）是平民和军事环境中发病和死亡率的主要原因。次要侮辱，例如具有出血性休克（HS）的多发性侮辱是常见的，尤其是在严重TBI的情况下，对预后有毁灭性的影响。脑部受伤的患者患有当前护理标准的脑部损坏患者易受到的低血压和脑水肿，并确定了对新方法的关键需求。 This application proposes to bring to IND a therapeutic, polynitroxylated pegylated hemoglobin (PNPH), which has been shown to be a unique neuroprotective hemoglobin that functioned as a small volume resuscitation solution that maximized hemodynamic stability, survival and brain tissue oxygen levels while minimizing neuronal death, after TBI plus HS in mice and outperformed the current standard of care for平民和军事前TBI复苏。