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

• 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
• 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; 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

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.

项目摘要/摘要 镰状细胞疾病（SCD）是一种影响全球数百万的遗传疾病。转基因SCD小鼠的研究 已经表明，SCD的特征是在粘附分子（高粘附）上过表达 内皮和血细胞。高粘附会导致血管阻塞，进而导致标志性急性 SCD的疼痛发作名为Vaso-Cocclusive Isises（VOC）。高粘附和VOC的关键参与者是 粘附分子p-选择素，将网状细胞和中性粒细胞缠绕到内皮中，并且很晚 抗原4（VLA-4），负责p-选择素下游的牢固粘附。中心挑战 SCD的临床管理是没有生物标志物，也没有直接可视化高粘附 人类。由于靶向粘附分子的新药，高粘附的知识不足是结果 为了防止VOC开发，但是没有生物标志物可以指导其使用。特别是SCD护理 提供者无法采用精确的医学方法来选择哪些患者会对P-选择蛋白有反应 Blocker Crizanlizumab仅在约50％的患者中有效，其成本很高，可能会导致严重 不良反应。该建议旨在通过开发有史以来图像的第一个生物标志物来推进该领域 通过成像激活的VLA-4，具有SCD的人类高粘附。我们假设正电子发射 VLA-4的层析成像（PET）成像将在治疗前测量高粘附，并且反应减少 抗刺激性药物。我们的多学科团队已经开发了宠物示踪剂64CU-CB-TE1A1P-PEG4- LLP2A（64CU-LLP2A）与激活的VLA-4结合。我们发现LLP2A可以检测到VLA-4介导的 SCD小鼠中对脂多糖（LPS）的响应高粘附，这种高粘附降低了 用抗P-选择蛋白mAb（类似于克里扎利珠单抗）处理。我们现在建议我）阐明 小鼠的其他高粘附（即hemin和缺氧）的其他触发因素更彻底地模拟人类病理学 （目标1）; ii）比较p-选择蛋白封锁后的小鼠中的64cu-llp2a吸收，而Voxelotor是一种新的FDA批准 用于靶向溶血并可能间接影响高粘附的SCD药物（AIM 2）； iii）对患者进行成像 使用SCD使用64CU-LLP2A，为此我们在2020年，治疗前后获得了监管机构的批准 与Crizanlizumab（目标3）。如果成功的话，我们的研究将为生物标志物驱动的精密医学铺平道路 以及对这一服务不足的患者的未来研究。反VOC治疗的未来临床试验可能 合并64CU-LLP2A来预测，量化和监视响应。