ACE2-targeted PET radiotracers for investigating spatiotemporal distribution of SARS-CoV-2 organ injury and therapy response.

ACE2 靶向 PET 放射性示踪剂用于研究 SARS-CoV-2 器官损伤和治疗反应的时空分布。

• 批准号: 10681427
• 负责人: Tejal A. Desai
• 金额: $ 80.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681427
• 关键词: 2019-nCoV; ACE2; Acceleration; Active Sites; Acute Respiratory Distress Syndrome; Angiotensin Receptor; Animals; Biochemical; Biocompatible Materials; Biodistribution; Biological Assay; COVID-19; COVID-19 pandemic; COVID-19 pandemic effects; COVID-19 treatment; Carboxypeptidase A; Central Nervous System; Cessation of life; Chemistry; Coronavirus Infections; Cryoelectron Microscopy; Development; Disease; Dose; Enzymes; Exposure to; Fluorides; Future; Gastrointestinal tract structure; Genetic Engineering; Goals; Heart; Heterogeneity; Human; Image; In Vitro; Infection; Infrastructure; Intravenous; Kidney; Knock-out; Label; Laboratories; Lead; Location; Lung; Mediating; Methods; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Organ; Pathogenesis; Patients; Peptides; Peptidyl-Dipeptidase A; Performance; Periodicity; Pharmaceutical Preparations; Physiological; Positron-Emission Tomography; Principal Investigator; Productivity; Proteins; Public Health; Publications; Publishing; Radioisotopes; Radiopharmaceuticals; Recombinants; Reporting; Resistance; Resolution; Route; SARS coronavirus; SARS-CoV-2 exposure; SARS-CoV-2 infection; SARS-CoV-2 spike protein; SARS-CoV-2 variant; Signal Transduction; Specificity; Structure; Techniques; Technology; Time; Tracer; Transgenic Mice; United States; Vaccines; Validation; Variant; Viral; Virus; Virus Diseases; Virus Receptors; Work; biosafety level 3 facility; chelation; cohort; coronavirus disease; dosimetry; fighting; imaging probe; improved; in vivo; infection rate; inhibitor; mortality; mouse model; nanoparticle; novel coronavirus; organ injury; preservation; protective effect; radiotracer; response to injury; spatiotemporal; therapeutically effective; tool; treatment effect; treatment response; vaccine distribution; vaccine-induced antibodies

PROJECT SUMMARY: The COVID-19 pandemic, caused by the new coronavirus SARS-CoV-2, has had a remarkable impact on public health worldwide with the largest number of cases and deaths reported in the United States. Improved understanding of COVID-19 will accelerate the development of effective therapeutics, which are necessary to fight SARS-CoV-2 including its new variants. The SARS-CoV-2 human receptor ACE2 is central to disease pathogenesis and potential therapies. This proposal focuses on the imaging and therapy of SARS-CoV-2 using a newly developed, ACE2-targeted PET radiotracer and S-protein neutralizing therapies. These therapies include PLGA nanoparticles bearing recombinant ACE2 (rACE2) and a monoclonal antibody (mAb) 5A6 recently developed at UCSF. Although the techniques and therapies proposed are directly applicable to SARS- CoV-2, they will also potentially apply to future coronavirus infections and other diseases driven by ACE2 suppression especially acute respiratory distress syndrome (ARDS). Therapies derived from ACE2 itself also have high impact in the context of SARS-CoV-2 variants that evade vaccines and mAb-based drugs. We recently identified a cyclic, [68Ga]-NOTA modified ACE2 inhibitory peptide ([68Ga]-NOTA-ACE2pep) as a PET radiotracer to study SARS-CoV-2 infection and its treatment in vivo. This radiotracer was developed with the goal of understanding the timing and location of ACE2 suppression in COVID-19, critical in treating infected patients and identifying disease in the lungs, heart, kidneys, gastrointestinal tract and central nervous system. ACE2-specific PET imaging will also help us understand the effects of rACE2/mAb therapies, whose development has lagged behind vaccine rollout. In this proposal, we will first optimize a radiosynthesis of an analogous 18F-labelled tracer namely [18F]AlF-NOTA-ACE2pep and validate its performance in vitro (Specific Aim 1). In Specific Aim 2, we use [18F]AlF-NOTA-ACE2pep to image ACE2 loss in transgenic mice and a COVID-19 murine model. Finally, in Specific Aim 3 we will develop nanoparticle-derived methods to deliver rACE2/ 5A6 and demonstrate suppression of SARS-CoV-2 infection, when therapy is administered around the time of exposure. This treatment effect will be shown in vivo using [18F]AlF-NOTA-ACE2pep. Our 3-year R01 proposal prioritizes methods and approaches that can be developed very quickly, in an effort to impact the COVID-19 pandemic as soon as possible. The principal investigators of this proposal are Drs. David M. Wilson, Robert Flavell, and Tejal Desai (UCSF) and Sanjay Jain (Johns Hopkins); as leaders in the field of infection imaging Drs. Wilson and Jain have worked extensively together. Key infrastructure is already in place at UCSF and Johns Hopkins for the fight against COVID-19. Specifically, Dr. Jain's BSL3 facility at Johns Hopkins is one of the few places in the world where the proposed PET-CT studies of SARS-CoV-2 infected animals can be performed. We will therefore harness the strengths of multiple productive laboratories at UCSF and Johns Hopkins to accomplish the proposed work.

项目概要： 由新型冠状病毒 SARS-CoV-2 引起的 COVID-19 大流行对 全球公共卫生状况有所改善，其中美国报告的病例和死亡人数最多。 对 COVID-19 的了解将加速有效疗法的开发，这对于 对抗 SARS-CoV-2，包括其新变种 SARS-CoV-2 人类受体 ACE2 是疾病的核心。 该提案重点关注 SARS-CoV-2 的成像和治疗。 一种新开发的、针对 ACE2 的 PET 放射性示踪剂和 S 蛋白中和疗法。 包括带有重组 ACE2 (rACE2) 和单克隆抗体 (mAb) 5A6 的 PLGA 纳米颗粒 尽管所提出的技术和疗法直接适用于 SARS- CoV-2，它们也有可能适用于未来的冠状病毒感染和由 ACE2 驱动的其他疾病 抑制尤其是急性呼吸窘迫综合征（ARDS）也源自 ACE2 本身。 在逃避疫苗和单克隆抗体药物的 SARS-CoV-2 变体的背景下具有重大影响。 我们最近鉴定了一种环状[68Ga]-NOTA 修饰的 ACE2 抑制肽（[68Ga]-NOTA-ACE2pep）作为 PET 放射性示踪剂用于研究 SARS-CoV-2 感染及其体内治疗。 了解 COVID-19 中 ACE2 抑制的时间和位置的目标，这对于治疗感染至关重要 患者并识别肺、心脏、肾脏、胃肠道和中枢神经系统的疾病。 ACE2特异性PET成像还将帮助我们了解rACE2/mAb疗法的效果，其 开发已经落后于疫苗的推出。在这项提案中，我们将首先优化一种疫苗的放射合成。 类似的 18F 标记示踪剂即 [18F]AlF-NOTA-ACE2pep 并验证其体外性能（具体 目标 1)。在具体目标 2 中，我们使用 [18F]AlF-NOTA-ACE2pep 对转基因小鼠中的 ACE2 损失进行成像。 最后，在特定目标 3 中，我们将开发纳米颗粒衍生的方法来交付。 rACE2/5A6 并证明当在周围进行治疗时可抑制 SARS-CoV-2 感染 这种治疗效果将使用我们的 3 年 R01 在体内显示。 提案优先考虑可以快速开发的方法和途径，以努力影响 COVID-19 尽快大流行。 该提案的主要研究者是 David M. Wilson 博士、Robert Flavell 和 Tejal Desai (UCSF) Wilson 和 Jain 博士是感染成像领域的领导者。 一般来说，加州大学旧金山分校和约翰霍普金斯大学已经准备好应对疫情的关键基础设施。 具体来说，Jain 博士位于约翰·霍普金斯大学的 BSL3 设施是世界上为数不多的几个可以提供这种服务的地方之一。 因此，我们将利用拟议的 SARS-CoV-2 感染动物的 PET-CT 研究。 加州大学旧金山分校和约翰霍普金斯大学的多个高效实验室的优势来完成拟议的工作。