Microfluidic Impedance Red Cell Assay (MIRCA) for Emerging Pharmacologic and Gene based Therapies for Sickle Cell Disease

微流控阻抗红细胞测定 (MIRCA) 用于镰状细胞病的新兴药理学和基因疗法

• 批准号: 10687427
• 负责人: Umut A. Gurkan
• 金额: $ 66.32万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687427
• 关键词: Abnormal Hemoglobins; Academia; Adhesives; Adoption; Affect; American; Basic Science; Biological Assay; Biological Markers; Biomedical Engineering; Biomimetics; Biophysics; Blood; Blood Banks; Blood Circulation; Blood Vessels; Blood specimen; Cell physiology; Cellular Assay; Clinic; Clinical; Clinical Trials; Collaborations; Development; Devices; Diabetes Mellitus; Disease; Endothelium; Engineering; Erythrocytes; Etiology; Event; Explosion; Feedback; Functional disorder; Gene therapy trial; Guidelines; Health; Hematological Disease; Hematologist; Hematology; Hereditary Disease; Hypoxia; Incentives; Individual; Inherited; Kidney Failure; Laboratories; Lesion; Malaria; Measurement; Measures; Methods; Microfluidic Microchips; Microfluidics; Modification; Monitor; Organ; Organ failure; Outcome; Pain; Pathologic; Pathology; Patient Care; Patient Monitoring; Patients; Pharmaceutical Preparations; Pharmacology; Physicians; Population; Property; Reporting; Reproducibility; Research Project Grants; Scientist; Selection for Treatments; Severity of illness; Sickle Cell Anemia; Surrogate Endpoint; Technology; Testing; Therapeutic; Training; Translating; Translations; Validation; Work; analytical tool; blood damage; design; diagnostic tool; electric impedance; experience; gene therapy; indexing; innovation; innovative technologies; instrumentation; microfluidic technology; mortality; novel; polymerization; portability; primary endpoint; prognostic value; tool; transfusion medicine; user-friendly; vaso-occlusive pain

PROJECT SUMMARY Acquired or inherited diseases can alter the red blood cell (RBC), causing severe clinical complications affecting the vasculature and organ health. Inherited red cell disorders, renal failure, diabetes, and blood bank storage lesions can all produce stiff, non-deformable RBCs. Red cell stiffness is particularly problematic in sickle cell disease (SCD), a debilitating inherited blood disorder. An estimated 100,000 individuals in the US, and millions more world-wide, have SCD. The field has experienced an explosion of novel SCD therapeutics, designed to target specific individual abnormalities in the RBC in the last five years. Numerous gene-based therapies intending to cure SCD are in clinical trials. This marked shift in SCD therapeutics produced a need for diagnostics and analytical tools that assess RBC health and quality. We need biomarkers of red cell function to serve as endpoints in clinical trials, assist in optimal drug selection and personalized monitoring for the individual, and to determine if gene-based therapy has normalized the red cell. Many aspects of the red cell must be assessed, but a key feature is deformability. There is a lack of robust, inexpensive devices sensitive enough to capture small populations of poorly deformable red cells able to continue to hemolyze, damage the blood vessels, and cause organ damage and early mortality. It is essential that we vet therapies for their ability to normalize the entire population of red cells. Here we propose to develop and translate the Microfluidic Impedance Red Cell Assay (MIRCA) to functionally measure red cell deformability, reported as Occlusion Index (OI) of a biomimetic microcapillary network array on a chip. We propose an innovative approach and a novel collaboration between engineers and a hematology-trained physician scientist. We will do so with the following steps: 1. We will achieve instrumentation and analytical validation of MIRCA measurement of red cell OI. Analytic validation will be performed both in PI’s laboratory (Dr. Umut Gurkan, CWRU) and in Co-I’s hematology laboratory (Dr. Vivien Sheehan, Emory) to prove generalizability and permit stakeholder feedback and design modification. 2. We will clinically validate MIRCA by assessing the association between OI and clinical complications and traditional laboratory measures of disease severity in SCD. 3. We will expand the use of the optimized MIRCA to the clinical space by demonstrating its prognostic value in longitudinal assessments of patients with SCD experiencing clinical complications and transitions in therapy. Using our unique collaboration between biomedical engineers and a hematology trained physician-scientist, we will optimize, validate, and achieve clinical adoption of MIRCA technology in clinical trials and patient care for individuals living with SCD in the US and world-wide.

项目概要 获得性或遗传性疾病会改变红细胞 (RBC)，导致严重的临床并发症 影响脉管系统和器官健康。遗传性红细胞疾病、肾功能衰竭、糖尿病和血库。 储存病变都会产生僵硬、不可变形的红细胞，红细胞僵硬在镰状细胞中尤其成问题。 细胞疾病 (SCD)，一种使人衰弱的遗传性血液疾病，美国估计有 100,000 人患有此病。 全球范围内有数百万人患有 SCD，该领域经历了新型 SCD 疗法的爆炸式增长， 旨在针对过去五年中众多基于基因的特定个体异常。 旨在治愈 SCD 的疗法正在进行临床试验，SCD 疗法的这一显着转变产生了对 SCD 的需求。 评估红细胞健康和质量的诊断和分析工具我们需要红细胞功能的生物标志物。 作为临床试验的终点，协助最佳药物选择和个体化监测， 并确定基于基因的治疗是否使红细胞正常化，必须对红细胞的许多方面进行检测。 评估，但一个关键特征是可变形性，缺乏足够灵敏的坚固、廉价的设备。 捕获少量不易变形的红细胞，能够继续溶血，损害血管， 并导致器官损伤和早期死亡，因此我们必须审查治疗方法使病情正常化的能力。 在这里，我们建议开发和转化微流体阻抗红细胞。 用于功能性测量红细胞变形性的测定 (MIRCA)，报告为仿生物质的闭塞指数 (OI) 我们提出了一种创新方法和一种新颖的合作。 我们将通过以下步骤来做到这一点： 1. 我们将实现红细胞 OI 分析的 MIRCA 测量的仪器化和分析验证。 验证将在 PI 实验室（CWRU Umut Gurkan 博士）和 Co-I 血液学中进行 实验室（Vivien Sheehan 博士，埃默里大学）证明普遍性并允许利益相关者反馈和设计 修改。 2. 我们将通过评估成骨不全与临床并发症之间的关联来对 MIRCA 进行临床验证 SCD 疾病严重程度的传统实验室测量。 3. 我们将通过展示其预后价值，将优化后的 MIRCA 的使用扩展到临床空间 对经历临床并发症和转变的 SCD 患者进行纵向评估 治疗。 利用我们生物医学工程师和受过血液学训练的医师科学家之间独特的合作， 我们将在临床试验和患者护理中优化、验证 MIRCA 技术并实现其临床采用 适用于美国和世界各地的 SCD 患者。