Rapid Reconstitution of a Lyophilized, Bio-inspired, Artificial Red Blood Cell

冻干仿生人造红细胞的快速重建

• 批准号: 10010242
• 负责人: Esma Alp
• 金额: $ 37.32万
• 依托单位: KALOCYTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010242
• 关键词: Address; Adverse effects; Affinity; Albumins; American; Authorization documentation; Benign; Blood; Blood Pressure; Blood Substitutes; Caring; Cell physiology; Characteristics; Clinical Trials Design; Collaborations; Colloids; Complex; Country; Department of Defense; Development; Environment; Erythrocytes; Event; Freeze Drying; Funding; Goals; Grant; Hemoglobin; Hemorrhage; Hemorrhagic Shock; Home environment; Hospitals; Human; Immune response; Individual; Industry; Intellectual Property; Lactated Ringer' s Solution; Life; Liquid substance; Lung; Nitric Oxide; Normal saline; Osmolalities; Osmolar Concentration; Oxygen; Patients; Phase; Physiological; Plasma; Plasmalyte A; Pre-hospitalization care; Process; Production; Publishing; Red Cross; Research; Resources; Resuscitation; Risk; Secure; Small Business Innovation Research Grant; Solid; Sterility; Testing; Therapeutic; Time; Tissues; Training; Transfusion; Translating; Trauma; Vascular blood supply; Water; Whole Blood; base; blood product; cost effective; crystalloid; design; expectation; experience; human study; in vivo; innovation; mass casualty; nanoencapsulated; operation; preclinical development; pressure; prevent; preventable death; prototype; rapid technique; reconstitution; transfusion medicine; vasoconstriction

PROJECT SUMMARY There is need for an artificial oxygen (O2) carrier to substitute for stored blood products, which at times are unavailable (pre-hospital care, austere environments, resource-limited countries), undesirable (risk of immune response), or in short supply to meet demand (mass casualty event). Moreover, transfusion of a crystalloid or colloid solution alone will lead to dilutional deficiencies of blood components such as red blood cells (RBCs), which are critical for delivering oxygen (O2) to the various tissues. KaloCyte's focus is to develop ErythroMer (EM), a lyophilized, bio-inspired, artificial RBC, which will transform how patients who need a transfusion are treated when stored RBCs or whole blood are not an option. Previous oxygen carrier products have had two major design flaws preventing them from mimicking RBC physiology: (1) inability to appropriately release O2 to tissues after capture in the lungs and (2) sequestration of nitric oxide (NO) resulting in vasoconstriction. EM is designed to not only carry O2 but also surmount the barriers encountered by prior oxygen carriers (intended as red blood cell substitutes). EM accomplishes this by emulating physiologic RBC O2 capture and delivery along with benign interaction with the vasculature. These key bio-inspired design features differentiate EM from previous attempts. Moreover, EM is designed for sterile lyophilization and so, is amenable to facile, rapid reconstitution after extended dry storage under ambient conditions. EM offers a pragmatic approach to a complex need and is designed for cost-effective production at scale. Our prototype has passed rigorous initial ex vivo and in vivo “proof of concept” testing. KaloCyte was founded so that we may translate EM innovations into a pragmatic therapeutic and as well as realize the commercial potential of a disruptive introduction into transfusion medicine. Our project goals are to enable rapid, facile reconstitution and establish the optimal colloid (albumin and freeze-dried plasma), and crystalloid (normal saline, lactated ringers, PlasmaLyte A) ratios for EM resuspension, while not disrupting the osmolality and oncotic pressure of blood. EM intellectual property is robust and secured by KaloCyte, which is supported by a solid research team, our CEO with a strong therapeutic industry background and scientific advisors, with experience in hemoglobin-based oxygen carrier development, lyophilization, transfusion medicine, hemorrhage & resuscitation, pre-clinical development and trial design. SBIR funding will enable KaloCyte to critical pre-clinical development in EM production and initiate groundwork required for IND authorization. Of note, our initial studies and the approach herein meet published FDA expectations for blood substitutes. Given the significant need and market potential we have hemorrhagic shock as the first indication for FDA approval. Following a successful trial for hemorrhagic shock, we would expand EM into other settings and exploit the design to extend efficacies beyond that of stored blood.

项目摘要 需要人工氧（O2）载体来替代储存的血液制品，所述血液制品有时被 不可用（院前护理、严峻的环境、资源有限的国家）、不受欢迎（免疫风险 反应），或供应短缺，以满足需求（大规模伤亡事件）。此外，输注晶体或 单独的胶体溶液将导致血液成分如红细胞（RBC）的稀释不足， 这对于将氧气（O2）输送到各种组织是至关重要的。KaloCyte的重点是开发ErythroMer (EM)这是一种冻干的、生物激发的人造红细胞，它将改变需要输血的患者的生活方式。 当储存的红细胞或全血不是一种选择时进行治疗。以前的氧载体产品有两个 主要的设计缺陷阻止它们模仿RBC生理学：（1）不能适当地释放O2， 在肺中捕获后的组织和（2）一氧化氮（NO）的隔离导致血管收缩。EM是 设计成不仅携带O2，而且克服现有氧载体（旨在作为 红细胞替代品）。EM通过模拟生理RBC O2捕获和输送沿着 与血管系统良性互动这些关键的生物灵感设计特征使EM与 以前的尝试。此外，EM被设计用于无菌冻干，因此，适合于方便、快速地冻干。 在环境条件下延长干燥储存后进行复溶。EM提供了一种务实的方法， 需要，并设计用于大规模的成本效益生产。我们的原型已经通过了严格的初始体外试验， 体内“概念验证”测试。KaloCyte的成立是为了将EM创新转化为 务实的治疗方法，并实现颠覆性引入输血的商业潜力 药我们的项目目标是使快速，简便的重建和建立最佳的胶体（白蛋白 和冻干血浆）和晶体（生理盐水、乳酸林格氏液、PlasmaLyte A）比率 重悬，同时不破坏血液的渗透压和渗透压。EM知识产权是强大的 并由KaloCyte担保，这是由一个坚实的研究团队支持，我们的首席执行官与强大的治疗 行业背景和科学顾问，具有血红蛋白氧载体开发经验， 冻干、输血药物、出血和复苏、临床前开发和试验设计。SBIR 资金将使KaloCyte能够在EM生产中进行关键的临床前开发，并启动基础工作 需要IND授权。值得注意的是，我们的初步研究和本文中的方法符合FDA公布的标准。 对血液替代品的期望考虑到巨大的需求和市场潜力， 作为FDA批准的第一个适应症。在失血性休克试验成功后，我们将扩大EM 并利用该设计将功效扩展到储存血液之外。