Endothelialized microfluidic assays for emerging therapies in sickle cell disease

用于镰状细胞病新兴疗法的内皮微流体检测

基本信息

批准号：
10476681
负责人：
Chiara Federici
金额：
$ 85.21万
依托单位：
BIOCHIP LABS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-05 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476681
关键词：
Abnormal Red Blood Cell Adhesions Adhesives American Anemia Antisickling Agents Biological Assay Biological Markers Biomimetics Blood Blood Cells Blood Transfusion Blood Vessels Cell Adhesion Clinical Clinical Research Complex Deoxygenated Sickle Hemoglobin Development Drug Screening Drug Targeting Economic Burden Endothelial Cells Endothelium Erythrocytes Exhibits Experimental Designs Functional disorder Goals Health Expenditures Hematological Disease Hemoglobin Hemoglobin concentration result Hypoxia Impairment In Vitro Individual Inflammation Inherited Ischemia Lactate Dehydrogenase Lead Letters Measurement Mediating Membrane Methodology Microfluidics Modernization Monitor Monoclonal Antibodies Morbidity - disease rate Organ P-Selectin Pain Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Physiological Polymers Priapism Procedures Property Quality Control Quality of life Reproducibility of Results Reticulocyte count Sampling Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Site Small Business Technology Transfer Research Standardization Stroke Technology Testing Therapeutic Thrombophilia Translating United States Food and Drug Administration Validation Variant Vascular Diseases Whole Blood acute chest syndrome base chromatin immunoprecipitation comorbidity design drug candidate drug discovery hydroxyurea in vitro Assay mortality novel novel therapeutics patient population patient response personalized medicine polymerization pre-clinical pre-clinical assessment precision drugs prevent response screening sickling social targeted agent targeted treatment tool vaso-occlusive crisis

项目摘要

PROJECT SUMMARY Sickle Cell Disease (SCD) afflicts 100,000 Americans and millions of people worldwide, and is characterized by anemia, painful vaso-occlusive crises, ischemia, inflammation, significant morbidity, and early mortality. In SCD, deoxygenated sickle hemoglobin (deoxy-HbS) polymerizes, deforms red blood cells (RBCs), changes membrane properties, and triggers inflammation, thrombophilia, and vasculopathy. Traditional treatment approaches include routine blood transfusions and hydroxyurea therapy while both options exhibit inherent challenges and limitations. Recent efforts in developing new treatment approaches in SCD focused on targeted therapies, aiming to prevent hypoxia-mediated polymerization of sickle hemoglobin and the abnormal adhesive interactions between blood and endothelial cells. Accordingly, the Food and Drug Administration (FDA) has recently approved two new treatments for SCD: ADAKVEO (Crizanlizumab, Novartis) and Oxbryta (Voxelotor, Global Blood Therapeutics) to prevent abnormal RBC adhesion and sickling. In addition to those, many other drug candidates targeting a specific adhesion pathway are currently in the development stage. Because SCD pathophysiology is extremely complex and heterogenous, it is crucial to predict how/if a patient will benefit from a specific targeted therapy. An anti-adhesive therapy may not benefit a certain patient population or may need to be supplemented with additional therapeutic approaches (i.e., anti-sickling drugs). Further, patient-specific responses to such therapies may be impacted by or associated with clinical variables (e.g., lactate dehydrogenase level, reticulocyte count, hemoglobin levels, etc.). Being able to predict a patient's response to a certain targeted therapy, or combination of multiple, using biomimetic in vitro tools will substantially help the entire SCD patient population. Therefore, there is an urgent need for novel biomimetic in vitro assays that can serve as a drug screening platform, both in understanding the effect of emerging therapies on a single patient level and in screening drug candidates for potential mitigation of SCD pathophysiology. Our objective in this STTR Phase I/II proposal is to develop a standardized and validated endothelialized microfluidic cellular adhesion assay to predict in vitro patient-specific responses to a targeted therapy by probing blood cell adhesion to activated endothelial cells. In Phase I, we propose to standardize and validate the culture and activation of endothelial cells as well as blood cell adhesion within the Endothelium-on- a-chip under physiologically relevant flow conditions. Phase II aims and milestones focus on activities related to determining baseline cellular adhesion levels, establishing the testing methodologies for proof-of-concept, and clinically validating the Endothelium-on-a-chip. Our goal is to demonstrate the utility of the Endothelium-on- a-chip in predicting patient-specific responses to single and combined targeted therapies in SCD.

项目概要镰状细胞病 (SCD) 困扰着 10 万美国人和全世界数百万人，其特点是贫血、痛苦的血管闭塞危象、缺血、炎症、显着的发病率和早期死亡。在SCD中，脱氧镰状血红蛋白 (deoxy-HbS) 聚合、使红细胞 (RBC) 变形、发生变化膜特性，并引发炎症、血栓形成倾向和血管病变。传统治疗方法包括常规输血和羟基脲治疗，而这两种选择都表现出固有的挑战和限制。最近在开发 SCD 新治疗方法方面的努力侧重于有针对性的旨在防止缺氧介导的镰状血红蛋白聚合和异常粘合剂的疗法血液和内皮细胞之间的相互作用。据此，美国食品药品监督管理局（FDA）最近批准了两种治疗 SCD 的新疗法：ADAKVEO（Crizanlizumab，诺华）和 Oxbryta（Voxelotor， Global Blood Therapeutics）防止异常红细胞粘附和镰状化。除了这些之外，还有很多其他的针对特定粘附途径的候选药物目前正处于开发阶段。因为SCD 病理生理学极其复杂且异质，预测患者如何/是否受益至关重要特定的靶向治疗。抗粘连治疗可能不会使某些患者群体受益，或者可能需要辅以其他治疗方法（即抗镰状化药物）。此外，针对患者的具体情况对此类疗法的反应可能受到临床变量的影响或与之相关（例如，乳酸脱氢酶水平、网织红细胞计数、血红蛋白水平等）。能够预测患者的反应使用仿生体外工具的某种靶向疗法或多种疗法的组合将极大地帮助整个 SCD 患者群体。因此，迫切需要新型仿生体外检测方法作为药物筛选平台，既可以了解新兴疗法对单个患者的影响水平和筛选潜在缓解 SCD 病理生理学的候选药物。我们在此 STTR I/II 期提案中的目标是开发标准化且经过验证的内皮化微流体细胞粘附测定预测体外患者对靶向治疗的特异性反应通过探测血细胞与活化内皮细胞的粘附。在第一阶段，我们建议标准化和验证内皮细胞的培养和活化以及内皮细胞内的血细胞粘附生理相关流动条件下的a-chip。第二阶段的目标和里程碑侧重于相关活动确定基线细胞粘附水平，建立概念验证的测试方法，以及临床验证芯片内皮细胞。我们的目标是展示内皮细胞的效用预测 SCD 患者对单一和联合靶向治疗的特定反应的芯片。