COVID-19: Ultrasound-microbubble targeted delivery of immuno-modulatory therapeutics to treat COVID-19

COVID-19：超声微泡靶向递送免疫调节疗法来治疗 COVID-19

• 批准号: 552687-2020
• 负责人: Botelho, Roberto
• 金额: $ 3.64万
• 依托单位: Ryerson University
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=703926
• 关键词: COVID; 19; Ultrasound; microbubble; targeted

COVID-19 caused by the novel coronavirus, SARS-CoV2, is now a historical pandemic due to its ease of transmission, potential to overburden our healthcare systems, and massive disruption to the global economy and everyday life. About 15% of COVID-19 patients require hospitalization and 5% intensive care, ultimately leading to 1-5% of individuals to succumb. The largest source of morbidity and mortality related to COVID-19 is the development of acute respiratory distress syndrome (ARDS) that arises from lung tissue damage and vascular leakage, leading to fluid-filled lungs that make breathing difficult. ARDS is not directly caused by the virus, but rather it is due to an over-reactive immune response known as cytokine release syndrome, or cytokine storm. This is caused by a molecular feedback loop that greatly amplifies inflammation causing general tissue damage. The main culprit for ARDS in COVID-19 seems to be the release of the inflammatory signal interleukin-6 (IL-6) and activation of its receptor (IL-6R). There is significant interest in interrupting IL-6R signaling as a way to abate inflammation and help patients recover. Potential treatments include anti-inflammatory drugs, neutralizing monoclonal antibodies, and RNA therapeutics. However, these drugs are delivered intravenously leading to global reduction of immune function and potential secondary infections. Targeted delivery and release of IL-6R inhibitors in the affected lung tissue would reduce side-effects. Ultrasound and microbubble technologies are emerging as potential workhorses to target the release of and/or stimulate the cellular uptake of therapeutics. Microbubbles are injected into the blood carrying a therapeutic payload, which are released in the presence of ultrasound field aimed at the affected tissue. Here, in collaboration with MD Precision Inc., a company that develops and makes ultrasound devices and applications, we aim to test the use of USMB to deliver silencing RNAs and neutralizing antibodies against IL-6R using cell lines and a mice model of ARDS. If promising, these results will form the basis for USMB applications to treat the worst symptoms of COVID-19, reducing morbidity, mortality, and alleviating pressure on hospitals.

由新型冠状病毒SARS-CoV 2引起的COVID-19现已成为历史性的大流行病，原因是其易于传播，可能使我们的医疗系统负担过重，并对全球经济和日常生活造成大规模破坏。约1 - 5%的COVID-19患者需要住院治疗，5%需要重症监护，最终导致1-5%的患者死亡。与COVID-19相关的发病率和死亡率的最大来源是肺组织损伤和血管渗漏导致的急性呼吸窘迫综合征（ARDS）的发展，导致肺部充满液体，呼吸困难。ARDS不是由病毒直接引起的，而是由于过度反应性免疫反应，称为细胞因子释放综合征或细胞因子风暴。 这是由一个分子反馈回路引起的，它极大地放大了炎症，导致一般组织损伤。COVID-19中ARDS的罪魁祸首似乎是炎症信号白细胞介素-6（IL-6）的释放及其受体（IL-6 R）的激活。人们对中断IL-6 R信号传导作为减轻炎症和帮助患者康复的一种方式非常感兴趣。潜在的治疗方法包括抗炎药物、中和性单克隆抗体和RNA疗法。然而，这些药物是静脉内递送的，导致免疫功能的全面降低和潜在的继发感染。IL-6 R抑制剂在受影响的肺组织中的靶向递送和释放将减少副作用。超声和微泡技术正在成为靶向释放和/或刺激细胞摄取治疗剂的潜在主力。将携带治疗有效载荷的微泡注射到血液中，在存在针对受影响组织的超声场的情况下释放微泡。在这里，与MD精密公司合作，作为一家开发和制造超声波设备和应用的公司，我们的目标是使用细胞系和ARDS小鼠模型测试USMB用于递送沉默RNA和针对IL-6 R的中和抗体的用途。如果有希望，这些结果将成为USMB应用于治疗COVID-19最严重症状的基础，降低发病率，死亡率并减轻医院压力。