An additive solution optimized for anaerobic (hypoxic) RBC storage to minimize storage lesion development.

一种针对厌氧（缺氧）红细胞储存进行优化的添加剂解决方案，可最大程度地减少储存损伤的发生。

• 批准号: 9908487
• 负责人: Travis Nemkov
• 金额: $ 72.19万
• 依托单位: NEW HEALTH SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908487
• 关键词: Adverse event; Age; Aging; Alkalinization; Altitude; Anaerobic Bacteria; Anemia; Animal Model; Animals; Biochemical; Biology; Blood; Blood Banks; Blood Transfusion; Blood Volume; Catalogs; Cellular Metabolic Process; Cryopreservation; Data; Development; Devices; Disease; Dose; Endothelial Cells; Energy Metabolism; Environment; Enzymes; Erythrocyte Transfusion; Erythrocytes; Evaluation; Excision; Exposure to; Formulation; Funding; Generations; Glyceraldehyde-3-Phosphate Dehydrogenases; Goals; Gold; Grant; Health; Health Sciences; Hemoglobin; Hemoglobin concentration result; Hemolysis; Hemorrhage; Hemorrhagic Shock; Hospitals; Hour; Human; Hypovolemic Shock; Hypoxia; Iatrogenesis; Inflammation; Intervention; Investigation; Iron; Label; Lesion; Licensing; Life; Liver; Logistics; Mass Spectrum Analysis; Measurement; Medical; Metabolic; Metabolic Marker; Metabolism; Mitochondria; Modeling; Molecular; Morphology; Organ; Outcome; Oxygen; Patients; Perfusion; Phase; Plasma; Procedures; Publishing; Rattus; Reaction; Reactive Oxygen Species; Recovery; Reducing Agents; Rejuvenation; Research Personnel; Resuscitation; Rodent Model; Safety; Sampling; Savings; Series; Severities; Shock; Small Business Innovation Research Grant; System; Technology; Testing; Time; Tissues; Transfusion; Trauma; Work; arm; base; clinically relevant; commercialization; design; experimental study; hemodynamics; improved; improved outcome; in vivo; innovation; insight; interest; man; metabolomics; novel; oxidant stress; oxidation; pre-clinical; predictive marker; prevent; research and development; response; scale up; screening; sex; tool; volunteer

The objective of this project is to develop an additive solution optimized for red blood cells (RBCs) stored under hypoxic environment, with the goal of producing highest quality RBCs by minimizing storage- associated damage (storage lesion). The additive solution developed in this project will be commercialized as a part of the Hemanext hypoxic storage platform. The proposal builds on the strong preliminary data showing that hypoxic storage of RBC (i) decreases oxidant stress and improves energy metabolism through mechanisms of intracellular alkalinization and concomitant removal of oxygen, a rate-limiting substrate for pro-oxidant reactions; (ii) promotes energy metabolism by preventing the oxidation of functional residues in key enzymes such as glyceraldehyde 3-phosphate dehydrogenase; (iii) significantly outperforms control RBCs with respect to the two FDA gold standard to determine storage quality, hemolysis and post-transfusion recovery; (iv) improves resuscitation (superior microvascular perfusion and oxygen delivery) in hemorrhaged rats, at significant lower doses than control RBCs and performing comparably to fresh RBCs even when end of storage hypoxic RBCs are transfused. In addition, hypoxic RBC reduces variability of quality present in the current products, while also reducing agents implicated in adverse events in the recipients. The potential for the development of storage additives tailored towards the specific metabolic needs of RBCs stored in the absence of oxygen became apparent from the wealth of data generated to test hypoxic storage for commercialization. Such an additive is expected to further improve RBC storage quality and promote transfusion outcomes in animal models. In order to develop such an additive and test the superiority of hypoxic RBCs stored in this new additive, the proposed project combines Hemanext’s extensive work over 10 years of research and development of hypoxic RBC storage platform (in part funded by SBIR Phase I, II and IIB grants), and Omix Technologies’ extensive published works on RBC metabolism in vivo and during blood bank storage. The three aims of this Phase II proposal are: First, to exploit innovative high-throughput metabolomics tools to optimize the formulation of five hypoxic additive solutions from candidates of 50+ additive formulations previously tested under normoxic storage. Additional formulations will be also examined that have been designed according to insights from RBC metabolism under hypoxic condition gathered from collaborative work over the past four years. Second, to scale up the development of the top performing additive formulation developed in aim 1, in order to determine storage quality under control and hypoxic storage in the new additive through the evaluation of hemolysis and 24-hour post-transfusion recovery studies in end of storage RBCs. Third, to further evaluate the potential efficacy of the top candidate additive solutions in a rodent model of hypovolemic shock and resuscitation. !

该项目的目标是开发一种针对红细胞 (RBC) 进行优化的添加剂解决方案 在低氧环境下储存，目的是通过最大限度地减少储存来生产最高质量的红细胞 相关损伤（储存损伤）。该项目开发的添加剂解决方案将实现商业化 作为 Hemanext 低氧存储平台的一部分。该提案建立在强有力的初步数据的基础上 表明红细胞的缺氧储存 (i) 可减少氧化应激并改善能量代谢 通过细胞内碱化和同时去除氧气的机制，限速 促氧化反应的底物； (ii) 通过防止氧化来促进能量代谢 关键酶如甘油醛3-磷酸脱氢酶中的功能残基； (三) 显着 在确定储存质量的两个 FDA 金标准方面优于对照红细胞， 溶血和输血后恢复； (iv) 改善复苏（卓越的微血管灌注 和氧气输送）在出血大鼠中，剂量显着低于对照红细胞并表现出 即使在输注储存结束时的缺氧红细胞时，其效果也与新鲜红细胞相当。另外，缺氧 RBC 减少了当前产品中存在的质量变异性，同时也减少了涉及的试剂 受者的不良事件。开发针对特定用途的储存添加剂的潜力 在无氧条件下储存的红细胞的特定代谢需求从财富中显而易见 为测试商业化的低氧储存而生成的数据。这种添加剂有望进一步 提高红细胞储存质量并促进动物模型中的输血结果。为了发展 并测试这种新添加剂中储存的缺氧红细胞的优越性，拟议的项目 结合了 Hemanext 10 年来在低氧红细胞储存方面的广泛研究和开发工作 平台（部分由 SBIR 第一、第二和 IIB 期拨款资助），以及 Omix Technologies 广泛发表的 作用于体内和血库储存期间的红细胞代谢。 第二阶段提案的三个目标是：第一，利用创新的高通量 代谢组学工具可优化 50 多种候选药物中的五种低氧添加剂溶液的配方 添加剂配方之前在常氧储存下进行过测试。额外的配方也将 根据缺氧条件下红细胞代谢的见解设计的检查 是从过去四年的协作工作中总结出来的。二是要加大发展力度 目标 1 中开发的顶级添加剂配方，以确定受控的储存质量 通过溶血和输血后 24 小时的评估来评估新添加剂中的缺氧储存 储存结束红细胞的回收率研究。三、进一步评估顶层的潜在功效 低血容量休克和复苏啮齿动物模型中的候选添加剂解决方案。 ！