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: 10490883
• 负责人: Tejal A. Desai
• 金额: $ 80.93万
• 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/10490883
• 关键词: 2019-nCoV; ACE2; 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; 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; Neuraxis; Organ; Pathogenesis; Patients; Peptides; Peptidyl-Dipeptidase A; Performance; Periodicity; Pharmaceutical Preparations; Physiological; Positron-Emission Tomography; Principal Investigator; 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 variant; Signal Transduction; Specificity; Structure; Techniques; Technology; Time; Tracer; Transgenic Mice; United States; Vaccines; Validation; Variant; Viral; Virus; Virus Diseases; Virus Receptors; Work; base; biosafety level 3 facility; chelation; cohort; coronavirus disease; dosimetry; fight against; 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.

项目摘要： 由新的冠状病毒SARS-COV-2引起的COVID-19大流行对 全球公共卫生在美国报告的病例和死亡人数最多。改进 对COVID-19的了解将加速有效疗法的发展，这对于 战斗SARS-COV-2，包括其新变体。 SARS-COV-2人体受体ACE2是疾病的核心 发病机理和潜在疗法。该提案着重于使用SARS-COV-2的成像和治疗 一种新开发的ACE2靶向宠物放射性固定剂和S蛋白中和疗法。这些疗法 包括带有重组ACE2（Race2）和单克隆抗体（MAB）5A6的PLGA纳米颗粒 最近在UCSF开发的。尽管提出的技术和疗法直接适用于SARS- COV-2，它们还将有可能应用于未来的冠状病毒感染和其他由ACE2驱动的疾病 抑制尤其是急性呼吸窘迫综合征（ARDS）。源自ACE2本身的疗法 在SARS-COV-2变体的背景下，逃避疫苗和基于MAB的药物的影响很大。 我们最近将一个循环[68GA] -NOTA修改了ACE2抑制性肽（[68GA] -NOTA-ACE2PEP） PET放射性示例研究SARS-COV-2感染及其在体内的治疗。这种放射性示例是由 了解Covid-19中ACE2抑制的时间和位置的目的，对治疗感染至关重要 患者并鉴定肺，心脏，肾脏，胃肠道和中枢神经系统中的疾病。 ACE2特定的宠物成像还将帮助我们了解Race2/mAb疗法的影响，谁 开发落后于疫苗推广。在此提案中，我们将首先优化 类似的18F标记示踪剂，即[18F] alf-nota-ace2pep并在体外验证其性能（具体 目标1）。在特定的目标2中，我们使用[18F] Alf-Nota-ace2pep来图像转基因小鼠和A中的ACE2损失 COVID-19鼠模型。最后，在特定目标3中，我们将开发纳米颗粒来源的方法来传递 Race2/ 5a6并在围绕治疗进行治疗时证明了SARS-COV-2感染的抑制 暴露时间。使用[18F] alf-nota-ace2pep在体内显示这种治疗效果。我们的3年R01 提案优先考虑可以很快开发的方法和方法，以影响 Covid-19尽快大流行。 该提案的主要研究人员是Drs。 David M. Wilson，Robert Flavell和Tejal Desai（UCSF） 和Sanjay Jain（Johns Hopkins）；作为感染成像领域的领导者。威尔逊和贾恩工作了 广泛在一起。 UCSF和约翰·霍普金斯（Johns Hopkins）已经建立了关键基础设施，以抗击 新冠肺炎。特别是Jain博士在约翰·霍普金斯（Johns Hopkins）的BSL3设施是世界上为数不多的地方之一 可以进行SARS-COV-2感染动物的拟议的PET-CT研究。因此，我们将利用 UCSF和Johns Hopkins的多个产品实验室的优势，完成了拟议的工作。