Clinical analysis and therapeutic development of exosomal ACE2

摘要 生物标记物引导的治疗是改善许多疾病预后的关键。当前的新冠肺炎大流行 由严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)引起的全球危机是由于滞后 接种疫苗和病毒控制不力，已造成2.53亿多例和510多万例 截至2021年11月15日的死亡人数。寻找可能感染易感人群或逃脱的潜在新毒株 从疫苗介导的预防，生物标记物引导的针对SARS广泛毒株的特定治疗- CoV-2以及未来的冠状病毒仍然是防止病毒传播和拯救人类生命的迫切需要 来自严重的新冠肺炎。新冠肺炎急性加重期患者血浆中可溶性成分的探讨 感染和恢复期，我们检测到ACE2在循环外切体的亚群中表达，并发现 血管紧张素转换酶2+外切体(ExoACE2)水平与新冠肺炎病情严重程度相关。纯化的ACE2+ 外切体通过抑制病毒刺突蛋白而竞争性阻断SARS-CoV-2感染 细胞受体ACE2。我们推测，胞外ACE2不仅是新冠肺炎的生物标志物 致病机制，但也代表了一种创新的诱饵疗法，以治疗所有使用ACE2的冠状病毒株 用于病毒入侵。我们提出了两个具体的目标：(1)建立外源ACE2的标准临床检测方法； 以及(2)开发针对当前和未来广泛的冠状病毒株的exoACE2疗法。二 学术机构(西北大学和MD安德森癌症中心)将与业界合作 合作伙伴ExoMira Medicine协作将exoACE2转化为临床应用，即生物标记物引导 治疗SARS-CoV-2和其他冠状病毒。

Abstract Biomarker-guided treatment is key to improve outcomes of many diseases. The current COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis due to lagged vaccination and inefficient control of the virus, which has caused over 253 million cases and more than 5.1 million deaths as of November 15, 2021. For potential new strains that may infect vulnerable populations or escape from vaccination-mediated prevention, biomarker-guided specific therapeutics against broad strains of SARS- CoV-2 as well as future corona viruses are still urgently required to prevent viral spreading and save human lives from severe COVID-19. In exploration of soluble components in the plasma of COVID-19 patients during acute infection and convalescent phase, we detected ACE2 expression in a subset of circulating exosomes and found that the levels of ACE2+ exosomes (exoACE2) are associated with severity of COVID-19. Purified ACE2+ exosomes competitively blocked the SARS-CoV-2 infection through inhibiting the viral Spike protein with its cellular receptor ACE2. We hypothesize that the exosomal ACE2 not only serves a biomarker for COVID-19 pathogenesis but also represents an innovative decoy therapy to treat all strains of coronaviruses that use ACE2 for viral entry. We propose two specific aims: (1) to establish a standard clinical assay for exoACE2 analysis; and (2) to develop exoACE2 therapeutics against the current and future broad strains of coronaviruses. Two academic institutions (Northwestern University and MD Anderson Cancer Center) will team up with the industry partner ExoMira Medicine for collaborative translation of exoACE2 into clinical applications, i.e. biomarker-guided therapy against SARS-CoV-2 and other coronaviruses.