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: 6190849
• 负责人: TIMOTHY C FISHER
• 金额: $ 28.33万
• 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/6190849
• 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：（研究者摘要）虽然红细胞（RBC） 输血是处理急性并发症的重要组成部分 镰状细胞病（SCD），最近的“STOP”研究表明， 长期输血可以预防高危SCD儿童的中风， SCD的输血存在以下问题：1）高同种免疫率（增加 至30%）和铁积累; 2）输血后限制 血细胞比容低于35%，以避免血液高粘滞， 导致血管闭塞然而，我们最近开发了一种 有可能缓解这些问题的技术：共价键合 将聚乙二醇（PEG）或相关聚合物的薄涂层涂在RBC上 面迄今为止的结果表明，由于涂覆，RBC表面 是抗体无法接近的（即，RBC血型抗原被“掩蔽”） 和红细胞相互作用，如红细胞聚集，最小化;后者的影响， 导致大大降低的低剪切血液粘度 包被红细胞可增加SS血中SS含量。 该研究计划的最终目标是开发安全和 有效的RBC聚合物包被方法， 粘度降低，并为镰状细胞提供治疗益处 疾病主题具体目标包括：1）优化聚合物涂层 通过评估线性、支化、星星和树枝状聚乙二醇分子的技术 以及各种键合化学和交联策略; 2）评价 聚合物包被的RBC在RBC形态方面的功能状态， 流变行为（即，变形性）、膜转运和氧 结合，鉴定受影响的膜蛋白（例如，C-14标记 PEG）、包被细胞的储存能力和小鼠体内存活率， 兔系统; 3）评价聚合物包被的RBC作为治疗剂， SCD通过M和SS RBC混合物在不同温度下的体外流变学研究 红细胞压积和氧张力，并通过在体内流动研究，使用大鼠 中盲肠和猫骨骼肌制备物; 4）聚合物的评价 包被作为防止同种异体免疫和/或保护输注的RBC的手段 在同种免疫的受试者中通过利用体外（例如，抗体/补体 结合、补体溶解、单核细胞单层测定）和体内方法 (e.g.,同种免疫兔模型、异种输血）方法。交互式 提出了实现这些目标的方法;它们的成功实现应该产生 重要的新数据和改善SCD的医疗保健。