POLYMER-COATED RED BLOOD CELL FOR SICKLE CELL DISEASE

用于镰状细胞病的聚合物涂层红细胞

• 批准号: 6390878
• 负责人: TIMOTHY C FISHER
• 金额: $ 26.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-28 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390878
• 关键词: biomaterial development /preparation; blood cell count; blood transfusion; blood viscosity; chemical bond; crosslink; disease /disorder model; erythrocyte membrane; erythrocytes; flow cytometry; histocompatibility; human tissue; laboratory mouse; laboratory rabbit; medical complication; membrane transport proteins; molecular film; oxygen tension; oxygen transport; polyethylene glycols; polymers; sickle cell anemia; striated muscles; surface coating

DESCRIPTION: (Investigator's abstract) Although red blood cell (RBC) transfusion is an essential component in the management of acute complications of sickle cell disease (SCD), and the recent "STOP" study has demonstrated that chronic blood transfusion can prevent stroke in high-risk SCD children, transfusion in SCD has associated problems: 1) high alloimmunization rates (up to 30 percent) and iron accumulation; 2) limitation of post-transfusion hematocrit to less than 35 percent to avoid blood hyperviscosity which may precipitate a vaso-occlusive event. However, we have recently developed a technique which has the potential to mitigate these problems: covalent bonding of a thin coating of polyethylene glycol (PEG) or related polymers to the RBC surface. Results to date indicate that consequent to coating, the RBC surface is inaccessible to antibodies (i.e., the RBC blood group antigens are "masked") and RBC interactions, such as RBC aggregation, are minimized; the latter effect results in greatly reduced low-shear blood viscosity even when the hematocrit of SS blood is increased with coated RBC. The ultimate objective of this Research Program is the development of safe and effective RBC polymer coating methods which achieve antigen masking and viscosity reduction and which offer therapeutic benefits for sickle cell disease subjects. Specific aims include: 1) optimizing polymer coating techniques via evaluating linear, branched, star and dendrimer PEG molecules and various bonding chemistries and crosslinking strategies; 2) evaluation of the functional status of polymer-coated RBC in terms of RBC morphology, rheological behavior (i.e., deformability), membrane transport and oxygen binding, identification of membrane proteins affected (e.g., C-14 labeled PEGs), the storage ability of coated-cells, and in vivo survival in mice and rabbit systems; 3) evaluation of polymer-coated RBC as therapeutic agents in SCD via in vitro rheologic studies of M and SS RBC mixtures at various hematocrits and oxygen tensions, and via in vivo flow studies using rat mesocecum and cat skeletal muscle preparations; 4) evaluation of polymer coating as a means to prevent alloimmunization and/or to protect transfused RBC in alloimmunized subjects by utilizing both in vitro (e.g., antibody/complement binding, complement lysis, monocyte monolayer assay) and in vivo approaches (e.g., alloimmunized rabbit model, xenotransfusions) methods. An interactive approach to these aims is proposed; their successful achievement should yield important new data and improved health care in SCD.

描述：（研究者的摘要）尽管红细胞（RBC） 输血是管理急性并发症的重要组成部分 镰状细胞疾病（SCD），最近的“停止”研究表明 慢性输血可以防止高危儿童中风， SCD中的输血有相关的问题：1）高质量免疫率（上升） 至30％）和铁的积累； 2）转化后的限制 血细胞比容降至35％以避免血液过度掩饰，这可能 促成一个血管熟悉的事件。但是，我们最近开发了 有可能减轻这些问题的技术：共价键合 聚乙烯乙二醇（PEG）或与RBC相关的聚合物的薄涂层 表面。迄今 抗体无法访问（即，RBC血组抗原被“掩盖”） RBC相互作用（例如RBC聚集）被最小化；后一种效果 即使血细胞比容，也会大大降低低剪切的血粘度 涂层的RBC增加了SS血液的血液。 该研究计划的最终目标是开发安全和 有效的RBC聚合物涂料方法，可实现抗原掩盖和 降低粘度并为镰状细胞带来治疗益处 疾病受试者。具体目的包括：1）优化聚合物涂料 通过评估线性，分支，恒星和树枝状聚合物PEG分子的技术 以及各种结合化的化学和交联策略； 2）评估 在RBC形态方面，聚合物涂层的RBC的功能状态， 流变行为（即可变形性），膜运输和氧气 结合，鉴定受影响的膜蛋白（例如，标记为C-14 钉），涂层细胞的存储能力以及小鼠和体内存活率 兔子系统； 3）评估聚合物涂层的RBC作为治疗剂 M和SS RBC混合物的体外流变研究在各种 血细胞比容和氧气张力，以及通过大鼠的体内流量研究 中菌和猫骨骼肌制剂； 4）评估聚合物 涂层作为防止同种免疫化和/或保护输血的RBC的一种手段 通过同时利用体外（例如抗体/补体），在同种免疫的受试者中 结合，补体裂解，单核细胞单层测定）和体内方法 （例如，同种免疫兔模型，异种转移）方法。互动 提出了这些目标的方法；他们成功的成就应该屈服 重要的新数据并改善了SCD的医疗保健。