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.

项目摘要镰状细胞病（SCD）遭受了全球100,000名美国人和数百万的人，其特征是贫血，疼痛的血管熟悉危机，缺血，炎症，明显的发病率和早期死亡率。在SCD中脱氧镰刀血红蛋白（脱氧-Hbs）聚合，变形红细胞（RBC），变化，变化膜特性以及触发炎症，血栓形成和血管病。传统待遇方法包括常规输血和羟基脲疗法，而两种选择都表现出固有的挑战和局限性。在SCD中开发新治疗方法的最新努力集中在目标上疗法，旨在防止缺氧介导的镰状血红蛋白和异常粘合剂的聚合血液和内皮细胞之间的相互作用。因此，食品和药物管理局（FDA）已有最近批准了SCD的两种新疗法：Adakveo（Crizanlizumab，Novartis）和Oxbryta（Voxelotor，，全球血液疗法）可防止异常的RBC粘附和可恶的疗法。除了其他许多针对特定粘附途径的候选药物目前处于开发阶段。因为SCD 病理生理学非常复杂且异质，预测患者如何受益至关重要特定的目标疗法。抗粘附疗法可能无法使某个患者群体受益或可能需要补充了其他治疗方法（即反ic脚药）。此外，特定于患者对这种疗法的反应可能会受到临床变量的影响或与临床变量有关（例如，乳酸脱氢酶水平，网状细胞计数，血红蛋白水平等）。能够预测患者对使用仿生体体外工具的某些靶向疗法或多种疗法的组合将基本帮助整个SCD患者人群。因此，迫切需要新型的仿生体体外测定法充当药物筛查平台，既了解新兴疗法对单个患者的影响水平和筛查候选药物的潜在减轻SCD病理生理学。我们在此STTR I/II阶段提案中的目标是开发标准化和经过验证的内皮化微流体细胞粘附测定法，以预测靶向治疗的体外患者特异性反应通过探测血细胞对活化的内皮细胞的粘附。在第一阶段，我们建议标准化和验证内皮细胞的培养和激活以及内皮内的血细胞粘附在生理相关的流动条件下的A芯片。第二阶段的目标和里程碑专注于与活动相关的活动确定基线细胞粘附水平，建立概念证明的测试方法，并临床验证片上的内皮。我们的目标是证明内皮的实用性 A-CHIP预测患者对SCD中单一和联合靶向疗法的患者特异性反应。