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：目前的COVID-19疫情是一场全球大流行病，有超过4500万例病例， 官方报告的死亡人数为120万。来自意大利的流行病学数据表明，40-96%的COVID-19 19例患者入院时发生ARDS和败血症。开发针对这些疾病的功能性治疗 条件也将有深远的影响，超越目前的流行病，因为潜在的病理学可以 由多种因素引起。 概述：该项目的目标是设计Tie 2超级激动剂纳米颗粒（NP）并优化其结构。 大规模生产。我们的纳米颗粒将用于治疗当前COVID-19病毒的致命症状 爆发急性呼吸窘迫综合征（ARDS）和脓毒症是COVID-19死亡率的主要原因。 目前还没有批准的药物来治疗这些疾病，因为靶受体的激活不能 控制在为了绕过这些限制，我们设计了一种从头蛋白质治疗剂， 制造和快速再生治疗ARDS和败血症所需的血管组织的主要限制。 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 NP超级激动剂克服了Ang 1的局限性，Ang 1是通过Tie 2发出信号的天然蛋白质， 不稳定，不能用作ARDS或脓毒症的有效治疗。拟议的供资将允许 立即开发NP以提高生物利用度并验证两种小鼠中的治疗效用 感染模型我们将在三个独立的目标中实现这一点：目标1：测量PK/PD、毒性和 聚乙二醇化Ang 1F-NP的体内免疫原性。目的2：研究Ang 1F纳米粒在C57 B1/6小鼠中的体内功效 感染H1N1-PR 8。目标3：验证Ang 1-NPs是否可以减少小鼠COVID-19/SARS的肺损伤- CoV-2感染。 智力优势：我们的目标是发展实验和技术进步，将产生强大的影响 在结构生物学，治疗发现和临床医学领域。我们正在与一个 少数能够接触到当前COVID-19菌株并正在积极开发动物疫苗的医疗分支机构 在临床试验之前测试疗法的模型。拟议的研究可能是一个关键的解决方案，以减少 这将有助于减少死亡总人数，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.