PET Imaging of Vaso-Occlussive Crisis in Sickle Cell Disease

项目总结/摘要 镰状细胞病（SCD）是一种遗传性疾病，影响全世界数百万人。转基因SCD小鼠的研究 已经表明，SCD的特征在于粘附分子在细胞表面的过度表达（超粘附）。 内皮和血细胞。粘连过度导致血管闭塞，进而导致标志性急性 SCD的疼痛发作称为血管闭塞性危象（VOC）。超粘附和VOC的关键参与者是 粘附分子P-选择素，其将网织红细胞和中性粒细胞系在内皮上， 抗原-4（VLA-4），负责P-选择素下游的牢固粘附。2010年的核心挑战是 SCD的临床管理是，在SCD患者中不存在生物标志物，也不存在直接可见的过度粘附。 人类对粘附过度的认识不足是必然的，因为靶向粘附分子的新药 防止挥发性有机化合物的方法正在开发中，但没有生物标志物来指导其使用。具体来说，SCD护理 提供者不能采用精确的医学方法来选择哪些患者会对P-选择素产生反应， 阻断剂crizanlizumab仅在约50%的患者中有效，成本高，并且可能导致严重的 不良反应.该提案旨在通过开发有史以来第一个用于成像的生物标志物来推进该领域 通过成像活化的VLA-4在患有SCD的人类中的过度粘附。我们假设正电子发射 VLA-4的断层扫描（PET）成像将在治疗前测量粘连过度， 抗粘连药物我们的多学科团队开发了PET示踪剂64 Cu-CB-TE 1A 1 P-PEG 4- LLP 2A（64 Cu-LLP 2A），其结合活化的VLA-4。我们发现LLP 2A可以检测VLA-4介导的 SCD小鼠中对脂多糖（LPS）应答超粘附，且超粘附通过 用抗P-选择素mAb（类似于crizanlizumab）治疗。我们现在建议i）阐明 小鼠中过度粘附的其他触发因素（即氯化血红素和缺氧），以更全面地模拟人类病理学 (Aim 1）; ii）比较P-选择素阻断后小鼠中的64 Cu-LLP 2A摄取与voxelotor，一种新的FDA批准 靶向溶血并可能间接影响粘附过度的SCD药物（目的2）;和iii）对患者进行成像 使用64 Cu-LLP 2A的SCD，我们于2020年获得监管批准，治疗前后 Crizanlizumab（Aim 3）。我们的研究如果成功，将为生物标记驱动的精准医学铺平道路。 和未来的研究。未来的抗VOC治疗临床试验可能 结合64 Cu-LLP 2A来预测、量化和监测响应。

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.