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

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.

项目总结/文摘