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

由新型冠状病毒SARS-CoV2引起的新冠肺炎现在是一场历史性的大流行，因为它易于传播，有可能使我们的医疗系统不堪重负，并对全球经济和日常生活造成巨大破坏。约15%的新冠肺炎患者需要住院治疗和5%的重症监护，最终导致1%-5%的患者死亡。与新冠肺炎相关的发病率和死亡率的最大来源是急性呼吸窘迫综合征的发展，急性呼吸窘迫综合征是由肺组织损伤和血管渗漏引起的，导致肺部充满液体，导致呼吸困难。ARDS不是由病毒直接引起的，而是由于一种被称为细胞因子释放综合征或细胞因子风暴的过度反应的免疫反应。这是由分子反馈回路引起的，该回路极大地放大了导致全身组织损伤的炎症。新冠肺炎急性呼吸窘迫综合征的罪魁祸首似乎是炎症信号白介素6(IL-6)的释放及其受体(IL-6R)的激活。作为一种消炎和帮助患者康复的方法，人们对阻断IL-6R信号非常感兴趣。可能的治疗方法包括抗炎药物、中和单抗和RNA疗法。然而，这些药物是通过静脉注射的，导致全球免疫功能下降和潜在的继发感染。在受影响的肺组织中靶向传递和释放IL-6R抑制剂将减少副作用。超声波和微泡技术正在成为靶向释放和/或刺激细胞吸收治疗药物的潜在主力。微泡被注入血液中，携带治疗有效载荷，在针对受影响组织的超声场中释放。在这里，我们与MD Precision Inc.合作，开发和制造超声波设备和应用程序，我们的目标是使用细胞系和ARDS的小鼠模型来测试USMB的使用，以传递针对IL-6R的沉默RNA和中和抗体。如果前景看好，这些结果将成为美联储应用于治疗新冠肺炎最严重症状的基础，从而降低发病率和死亡率，并缓解医院的压力。

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.