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: 6650218
• 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/6650218
• 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) 输血是治疗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 儿童中风， SCD 中的输血具有相关问题：1）高同种免疫率（高达 至 30%）和铁积累； 2) 输血后的限制 血细胞比容低于 35%，以避免血液高粘度，这可能 引发血管闭塞事件。不过，我们最近开发了一个 有可能缓解这些问题的技术：共价键合 在红细胞上涂上一层薄薄的聚乙二醇 (PEG) 或相关聚合物 表面。迄今为止的结果表明，涂​​层后，红细胞表面 抗体无法接近（即红细胞血型抗原被“掩盖”） 红细胞相互作用（例如红细胞聚集）被最小化；后一个效果 即使血细胞比容降低，低剪切血液粘度也会大大降低 SS 血液随着包被红细胞而增加。 该研究计划的最终目标是开发安全和 有效的红细胞聚合物涂层方法，可实现抗原掩蔽和 降低粘度，为镰状细胞病提供治疗益处 疾病科目。具体目标包括：1）优化聚合物涂层 通过评估线性、支化、星形和树枝状 PEG 分子的技术 以及各种化学键合和交联策略； 2）评价 聚合物包被的红细胞在红细胞形态方面的功能状态， 流变行为（即变形性）、膜传输和氧气 结合，受影响的膜蛋白的鉴定（例如，C-14 标记 PEG）、包被细胞的储存能力以及小鼠体内的存活率和 兔子系统； 3) 聚合物涂层红细胞作为治疗药物的评价 通过在不同条件下对 M 和 SS 红细胞混合物进行体外流变学研究进行 SCD 血细胞比容和氧张力，并通过大鼠体内血流研究 盲肠系膜和猫骨骼肌制剂； 4)聚合物的评价 涂层作为防止同种免疫和/或保护输血红细胞的手段 在同种免疫受试者中，通过利用体外（例如，抗体/补体 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、异种输血）方法。一个互动的 提出了实现这些目标的方法；他们的成功成就应该产生 重要的新数据和改善 SCD 的医疗保健。