Clinical analysis and therapeutic development of exosomal ACE2

摘要 生物标志物指导治疗是改善许多疾病预后的关键。当前的COVID-19疫情 严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）引起的全球性危机， 疫苗接种和病毒控制不力，已造成超过2.53亿例和510多万例病例， 截至2021年11月15日。对于可能感染脆弱人群或逃逸的潜在新菌株 从疫苗介导的预防，生物标志物指导的针对SARS广泛菌株的特异性治疗， CoV-2以及未来的冠状病毒仍然迫切需要防止病毒传播和拯救人类生命 严重的COVID-19。探索COVID-19患者急性期血浆中的可溶性成分 在感染和恢复期，我们检测了循环外泌体亚组中ACE 2的表达， ACE 2+外泌体（exoACE 2）的水平与COVID-19的严重程度相关。纯化ACE 2 + 外泌体通过抑制SARS-CoV-2病毒刺突蛋白， 细胞受体ACE 2。我们假设外泌体ACE 2不仅是COVID-19的生物标志物， 但也代表了一种创新的诱饵疗法，用于治疗所有使用ACE 2的冠状病毒株 病毒进入。我们提出了两个具体目标：（1）建立exoACE 2分析的标准临床分析方法; 和（2）开发针对当前和未来的冠状病毒广泛株的exoACE 2治疗剂。两 学术机构（西北大学和MD安德森癌症中心）将与该行业合作 合作伙伴ExoMira Medicine将exoACE 2协作转化为临床应用，即生物标志物引导 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.