De Novo Designed Protein Nanoparticle Agonists Targeting the Tie2 Receptor for the Treatment of ARDS and Sepsis in Patients with COVID-19

更广泛的影响：当前的新冠肺炎疫情是一场全球大流行，有4500多万病例和 官方报告的死亡人数为120万人。来自意大利的流行病学数据表明，40%-96%的COVID- 入院的19名患者出现ARDS和败血症。开发一种治疗这些疾病的功能性疗法 这种情况还将产生除当前大流行之外的深远影响，因为潜在的病理可能 产生于多种因素。 概述：本项目的目标是设计一种Tie2超激动剂纳米颗粒(NP)并优化其 大规模生产。我们的NPS将被用来治疗目前新冠肺炎病毒的致命症状 疫情爆发。急性呼吸窘迫综合征和脓毒症是新冠肺炎死亡的主要原因。 目前还没有被批准的治疗这些疾病的药物，因为靶受体的激活不能 被控制住。为了绕过这些限制，我们设计了一种从头蛋白疗法，它克服了 治疗ARDS和脓毒症所需的血管组织的制造和快速再生的主要限制。 这种技术可以减轻患者进入诊所或隔离时感染COVID的危险。我们的 NP超级激动剂克服了Ang1的局限性，Ang1是一种通过Tie2传递信号的天然蛋白质，它也 不稳定用于ARDS或脓毒症的有效治疗。拟议的资金将允许 立即开发NP以提高生物利用度并在两只小鼠身上验证治疗效果 感染模型。我们将通过三个不同的目标来实现这一点：目标1：测量PK/PD、毒性和 聚乙二醇化Ang1F-NP体内免疫原性研究目的2：验证Ang1F纳米粒对C57BL/6小鼠的体内效应 感染H1N1-PR8病毒。目的3：验证血管紧张素-1纳米粒对新冠肺炎/非典型肺炎小鼠肺损伤的保护作用 冠状病毒2型感染。 智力优势：我们的目标是发展将产生强大影响的实验和技术进步 在结构生物学、治疗发现和临床医学领域。我们正在与一家 很少有医学分支机构能够接触到当前的新冠肺炎毒株，并且正在积极开发动物 在临床试验之前测试治疗方法的模型。这项拟议的研究可能是减少 减少死亡总人数，并使医疗保健专业人员能够更好地治疗病毒爆发患者。

Broader Impacts: The current COVID-19 outbreak is a global pandemic with over 45 million cases and 1,200,000 deaths officially reported. Epidemiological data emerging from Italy indicate that 40-96% of COVID- 19 patients admitted into the hospital develop ARDS and sepsis. Developing a functional treatment for these conditions would also have far reaching impacts beyond this current pandemic, as the underlying pathology can arise from a multitude of factors. Overview: The goal of this project is to engineer a Tie2 super-agonistic nanoparticle (NP) and optimize its production at large scale. Our NPs would be used to treat the lethal symptoms of the current COVID-19 viral outbreak. Acute respiratory distress syndrome (ARDS) and sepsis are major contributors to COVID-19 mortality. Currently there are no approved drugs to treat these conditions, because activation of the target receptors cannot be controlled. To bypass these limitations, we engineered a de novo protein therapeutic that overcomes the major limitations of manufacturing and rapid regeneration of vascular tissue needed to treat ARDS and sepsis. Such a technology could mitigate the dangers of COVID infection when patients enter clinics or quarantine. Our NP super-agonist overcomes the limitations of Ang1, the natural protein that signals through Tie2, which is too unstable to be used as an effective treatment for ARDS or sepsis. The proposed funding would allow for immediate development of the NP to improve bioavailability and validation of therapeutic utility in two murine infection models. We will achieve this in three separate aims: Aim 1: Measure PK/PD, Toxicity and Immunogenicity of Pegylated Ang1F-NP In Vivo. Aim 2: Validate In Vivo Efficacy of Ang1F NPs in C57Bl/6 mice infected with H1N1-PR8. Aim 3: Validate Whether Ang1-NPs Reduce Lung Injury in Murine COVID-19/SARS- CoV-2 Infection. Intellectual Merit: We aim to develop experimental and technological advances that will have a strong impact in the fields of structural biology, therapeutic discovery, and clinical medicine. We are working with one of the few medical branches that have access to the current COVID-19 strain and who are actively developing animal models to test out therapies prior to clinical trials. The proposed research could be a key solution to reduce the total number of deaths and enable healthcare professionals to better treat patients suffering from viral outbreaks.