A Receptor-Targeted Nanoparticle PET Tracer in Human Carotid Atherosclerosis

人颈动脉粥样硬化受体靶向纳米粒子 PET 示踪剂

• 批准号: 10671549
• 负责人: Pamela K Woodard
• 金额: $ 70.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671549
• 关键词: Aftercare; Anatomy; Arterial Fatty Streak; Biology; Blood Platelets; Blood Vessels; C-Type Natriuretic Peptide; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Carotid Endarterectomy; Carotid Stenosis; Cell Lineage; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Complex; Consensus; Data; Detection; Diameter; Disease; Endothelium; Event; Evolution; Funding; G-Protein-Coupled Receptors; Gene Expression; Goals; Grant; Guidelines; Health Care Costs; Human; Hyperplasia; Hypertension; Image; Imaging Techniques; Immunohistochemistry; Individual; Infiltration; Inflammation; Intervention; Interview; Ipsilateral; Ischemia; Ischemic Stroke; Length; Ligands; Macrophage; Magnetic Resonance Imaging; Medical; Molecular; Morphology; Natriuretic Peptides; Observational Study; Operative Surgical Procedures; Outcome Assessment; Outcome Study; Patient-Focused Outcomes; Patients; Peptide Receptor; Perioperative; Physiological; Positron-Emission Tomography; Predictive Value; RNA; Recommendation; Regulation; Research; Risk; Risk Marker; Role; Rupture; Shapes; Signal Transduction; Smooth Muscle Myocytes; Specimen; Surgeon; Symptoms; Telephone; Testing; Tracer; United States; United States National Institutes of Health; Universities; Vascular Smooth Muscle; Vascular remodeling; Washington; Work; X-Ray Computed Tomography; atherosclerosis risk; cell type; cerebrovascular; chelation; cohort; diabetes management; differential expression; first-in-human; fluorodeoxyglucose; high risk; human study; hypertension control; imaging approach; immunoregulation; molecular imaging; nanoparticle; novel; patient stratification; radiotracer; receptor; risk stratification; routine screening; stroke risk; transcriptomics; uptake; vascular smooth muscle cell proliferation

PROJECT SUMMARY Currently no consensus exists in clinical guidelines for management of patients with asymptomatic carotid artery stenosis (ACAS). Some guidelines recommend carotid endarterectomy (CEA) surgery for patients with ACAS of ≥ 60% diameter. However, it is argued that 95% of all surgical interventions for ACAS in the United States may be unnecessary, generating needless healthcare costs of >$2 billion annually. Our goal in this proposal is to study plaque biology in ACAS patients through PET imaging at the molecular level to help identify individuals who are at 'higher-risk’ for ischemic stroke from plaque rupture and may benefit from carotid surgical intervention. We propose a 2-center patient outcomes study that expands upon data and observations from our earlier single center first-in-human study at Washington University using a nanoparticle PET radiotracer that targets the natriuretic peptide receptor C (NPRC) to determine if it can be used to risk stratify patients with ‘higher-risk’ ACAS. We and others have shown that NPRC is expressed at higher levels in complex plaques with features of vulnerability in patients with ACAS. In our most recent NIH R01-funded proof-of-concept study in a cohort of 42 patients with ACAS, we have shown linear correlation between 64Cu-CANF-Comb PET radiotracer uptake and features of high-risk plaque and correlative 64Cu-CANF-Comb PET uptake to the presence of NPRC in CEA specimens of patients who underwent surgery. We propose the following Specific Aims: Aim 1. To determine the ability of 64Cu-CANF-Comb PET to risk stratify ACAS patients treated with optimal medical therapy (OMT) alone with respect to patient outcomes. In this observational study, 80 patients with ACAS ≥ 60% will undergo 64Cu-CANF-Comb PET/MRI. Patients will be maintained on either OMT alone or receive OMT and CEA as determined by their treating vascular surgeon prior to imaging. OMT will consist of antiplatelet, statin, and hypertension and diabetes management when applicable. All patients will be evaluated with phone interviews every 3 months for a minimum of 18 months to assess for ipsilateral ischemic cerebrovascular event. PET signal will be assessed as a marker of risk for event or progression to CEA in comparison to anatomic features of vulnerable plaque on MRI, with the goal of determining a PET signal threshold which suggests higher risk ACAS. Aim 2: To further understand the role of NPRC in the evolution of carotid atherosclerosis. A. Patients treated with OMT alone will undergo repeat PET/MRI at 18 months, or earlier if they develop symptoms. PET/MRI changes over the 18-month interval will be used to further understand the biology of carotid plaque evolution after treatment with OMT. B. In patients who initially undergo CEA, PET signal will be compared to ex vivo plaque vulnerability and NPRC cellular distribution to facilitate understanding of gene expression using immunohistochemistry (IHC) and cell origin through single cell RNA/CITE-seq transcriptomics. Results will provide information on the potential of a new imaging approach, 64Cu-CANF-Comb PET, to risk stratify patients with ACAS and reveal mechanistic information about the role of NPRC in plaque vulnerability and inflammation.

项目概要 目前无症状颈动脉患者的治疗临床指南尚无共识 一些指南建议对 ACAS 患者进行颈动脉内膜切除术 (CEA) 手术。 然而，有人认为，美国 95% 的 ACAS 手术干预都可能发生。 是不必要的，每年产生超过 20 亿美元的不必要的医疗费用。 通过分子水平 PET 成像研究 ACAS 患者的斑块生物学，以帮助识别个体 因斑块破裂而患缺血性中风“风险较高”的人可能会受益于颈动脉手术干预。 我们提出了一项 2 中心患者结果研究，该研究扩展了我们早期单一研究的数据和观察结果 华盛顿大学中心首次进行人体研究，使用纳米粒子 PET 放射性示踪剂，针对 利钠肽受体 C (NPRC) 以确定是否可用于对“高风险”患者进行风险分层 我们和其他人已经证明，NPRC 在具有特征的复杂斑块中表达水平较高。 在我们最近由 NIH R01 资助的一组概念验证研究中，我们发现了 ACAS 患者的脆弱性。 42 名 ACAS 患者，我们显示了 64Cu-CANF-Comb PET 放射性示踪剂摄取之间的线性相关性 高风险斑块的特征以及 64Cu-CANF-Comb PET 摄取与 CEA 中 NPRC 存在的相关性 我们提出以下具体目标： 目标 1. 确定 64Cu-CANF-Comb PET 对接受最佳药物治疗的 ACAS 患者进行风险分层的能力 (OMT) 单独与患者结果相关 在这项观察性研究中，80 名 ACAS ≥ 60% 的患者将。 接受 64Cu-CANF-Comb PET/MRI 的患者将继续接受单独的 OMT 治疗或接受 OMT 和 CEA 治疗。 由血管外科医生在成像前确定，OMT 将包括抗血小板药物、他汀类药物和 高血压和糖尿病管理（如适用）将通过电话访谈进行评估。 每 3 个月评估一次，至少持续 18 个月，以评估同侧缺血性脑血管事件。 与以下疾病的解剖特征相比，将被评估为事件或进展为 CEA 的风险标志 MRI 上的易损斑块，目的是确定表明 ACAS 风险较高的 PET 信号阈值。 目标 2：进一步了解 NPRC 在颈动脉粥样硬化演变中的作用 A. 患者。 单独接受 OMT 治疗的患者将在 18 个月时再次接受 PET/MRI，如果出现症状则更早。 18 个月间隔内的变化将用于进一步了解颈动脉斑块进化的生物学 B. 在最初接受 CEA 的患者中，PET 信号将与离体斑块进行比较。 脆弱性和 NPRC 细胞分布，以促进使用 通过单细胞 RNA/CITE-seq 转录组学进行免疫组织化学 (IHC) 和细胞起源分析。 提供有关新成像方法 64Cu-CANF-Comb PET 对患者进行风险分层的潜力的信息 与 ACAS 合作，揭示有关 NPRC 在斑块脆弱性和炎症中作用的机制信息。