PET Imaging of Vaso-Occlussive Crisis in Sickle Cell Disease

镰状细胞病血管闭塞危象的 PET 成像

基本信息

批准号：
10366801
负责人：
Carolyn J. Anderson
金额：
$ 76.31万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366801
关键词：
Acute Acute Pain Address Adhesions Adopted Adverse reactions Affect Aftercare Antibodies Attenuated Binding Biological Markers Blood Blood Cells Blood Vessels Cell Adhesion Molecules Chronic Clinical Management Clinical Research Clinical Trials Consequentialism Dangerousness Disease Drug Targeting Endothelial Cells Endothelium Erythrocytes FDA approved Future Genetic Diseases Grant Hemin Hemoglobin Hemoglobinopathies Hemolysis Histology Human Human Pathology Hypoxia Image Inflammatory Inherited Institutional Review Boards Integrin alpha4beta1 Integrins Ischemia Knowledge Link Lipopolysaccharides Lung Measurement Measures Mediating Microfluidics Minority Groups Molecular Monitor Monoclonal Antibodies Morbidity - disease rate Mus Mutate Mutation Names Oxidative Stress P-Selectin Pain Patient imaging Patients Persons Pharmaceutical Preparations Positron-Emission Tomography Process Prophylactic treatment Recording of previous events Research Resort Reticulocytes Risk Role Seminal Sickle Cell Anemia Testing Therapeutic Time Tracer Transgenic Organisms Treatment Efficacy Underserved Population Visualization alternative treatment analog base bench to bedside beta Globin biomarker-driven bone care providers clinical care cost drug development experimental study human model imaging biomarker in vivo inflammatory marker molecular imaging mortality multidisciplinary neutrophil new therapeutic target novel drug class overexpression precision medicine prevent public health relevance quantitative imaging response safety and feasibility targeted imaging translational potential treatment trial two photon microscopy underserved minority uptake vaso-occlusive crisis

项目摘要

Project Summary/Abstract Sickle cell disease (SCD) is a genetic disorder that affects millions worldwide. Research in transgenic SCD mice has shown that SCD is characterized by the overexpression of adhesion molecules (hyperadhesion) on the endothelium and blood cells. Hyperadhesion causes vascular occlusion, which in turn leads to the hallmark acute pain episodes of SCD named vaso-occlusive crises (VOC). Key players in hyperadhesion and VOC are the adhesion molecules P-selectin, that tethers reticulocytes and neutrophils to the endothelium, and Very Late Antigen-4 (VLA-4), that is responsible for firm adhesion downstream of P-selectin. The central challenge in the clinical management of SCD is that there exist no biomarkers nor direct visualization of hyperadhesion in humans. The knowledge deficit on hyperadhesion is consequential, as new drugs targeting adhesion molecules to prevent VOC are being developed, yet there are no biomarkers to guide their use. Specifically, SCD care providers cannot adopt a precision medicine approach to select which patients will respond to the P-selectin blocker crizanlizumab, which is only efficacious in ~50% of patients, carries a high cost, and may cause severe adverse reactions. This proposal aims to advance the field by developing the first-ever biomarker to image hyperadhesion in humans with SCD by imaging activated VLA-4. We hypothesize that positron emission tomography (PET) imaging of VLA-4 will measure hyperadhesion before treatment, and its decrease in response to anti-hyperadhesive drugs. Our multidisciplinary team has developed the PET tracer 64Cu-CB-TE1A1P-PEG4- LLP2A (64Cu-LLP2A) that binds to activated VLA-4. We found that LLP2A can detect VLA-4-mediated hyperadhesion in response to lipopolysaccharide (LPS) in SCD mice, and that hyperadhesion is reduced by treatment with anti-P-selectin mAb (analogous to crizanlizumab). We now propose to i) elucidate the role of additional triggers of hyperadhesion (i.e. hemin and hypoxia) in mice, to more thoroughly model human pathology (Aim 1); ii) to compare 64Cu-LLP2A uptake in mice after P-selectin blockade vs. voxelotor, a new FDA-approved drug for SCD that targets hemolysis and may impact hyperadhesion indirectly (Aim 2); and iii) to image patients with SCD using 64Cu-LLP2A, for which we were granted regulatory approval in 2020, before and after treatment with crizanlizumab (Aim 3). Our studies, if successful, will pave the way for biomarker-driven precision medicine and future research for this underserved group of patients. Future clinical trials of anti-VOC treatments may incorporate 64Cu-LLP2A to predict, quantify, and monitor response.

项目概要/摘要镰状细胞病 (SCD) 是一种影响全球数百万人的遗传性疾病。转基因 SCD 小鼠的研究已经表明，SCD 的特点是粘附分子（过度粘附）在内皮细胞和血细胞。过度粘附会导致血管闭塞，进而导致标志性的急性 SCD 的疼痛发作称为血管闭塞危象 (VOC)。超粘附和 VOC 的关键参与者是粘附分子 P-选择素，将网织红细胞和中性粒细胞束缚于内皮细胞，以及 Very Late 抗原 4 (VLA-4)，负责 P-选择素下游的牢固粘附。的核心挑战是 SCD 的临床管理是不存在生物标志物，也不存在直接可见的过度粘连人类。随着针对粘附分子的新药的出现，对过度粘附的知识缺乏是必然的防止 VOC 的方法正在开发中，但尚无生物标志物来指导其使用。具体而言，SCD 护理提供者无法采用精准医学方法来选择哪些患者将对 P-选择素有反应阻断剂 crizanlizumab 仅对约 50% 的患者有效，成本高昂，并可能导致严重的并发症不良反应。该提案旨在通过开发第一个用于成像的生物标志物来推进该领域的发展通过成像激活的 VLA-4 观察患有 SCD 的人类的过度粘附。我们假设正电子发射 VLA-4 的断层扫描 (PET) 成像将测量治疗前的过度粘附及其反应的降低抗过度粘附药物。我们的多学科团队开发了 PET 示踪剂 64Cu-CB-TE1A1P-PEG4- LLP2A (64Cu-LLP2A) 与激活的 VLA-4 结合。我们发现LLP2A可以检测VLA-4介导的 SCD 小鼠对脂多糖 (LPS) 的过度粘附反应，并且通过以下方法可以减少过度粘附使用抗 P-选择素单克隆抗体（类似于 crizanlizumab）治疗。我们现在建议 i) 阐明以下角色：小鼠过度粘附的其他触发因素（即血红素和缺氧），以更彻底地模拟人类病理学（目标 1）； ii) 比较 P-选择素阻断后小鼠与 voxelotor（FDA 批准的新药物）对 64Cu-LLP2A 的摄取情况针对溶血并可能间接影响过度粘附的 SCD 药物（目标 2）； iii) 对患者进行成像使用 64Cu-LLP2A 进行 SCD，我们于 2020 年获得监管部门批准，治疗前后与 crizanlizumab（目标 3）。我们的研究如果成功，将为生物标志物驱动的精准医学铺平道路以及针对这一服务不足的患者群体的未来研究。未来抗挥发性有机化合物治疗的临床试验可能结合 64Cu-LLP2A 来预测、量化和监测反应。