Phase 1/2a Clinical Study of Descartes-30 in Acute Respiratory Distress Syndrome

摘要 这一应用是为了支持首个mRNA工程细胞疗法治疗急性白血病的临床试验。 呼吸窘迫综合征，包括新冠肺炎引起的呼吸窘迫综合征。美国食品和药物管理局已经 已经审查了IND的申请，并确定可以继续进行研究。ARDS是一家 估计每年有8万美国人死于严重的炎症性呼吸衰竭。80% 的ARDS患者需要机械通气。目前还没有FDA批准的ARDS疗法 可用。ARDS可由感染性或非感染性(如创伤性或化学性)侮辱引起。 新冠肺炎是目前导致急性呼吸窘迫综合征最常见的原因，而绝大多数新冠肺炎 死亡原因是急性呼吸窘迫综合征。中性粒细胞胞外陷阱(Net)驱动过度活跃 急性呼吸窘迫综合征和新冠肺炎的炎症反应以及Net的存在与 ARDS的严重性。蚊帐是由当地贩卖的中性粒细胞经历蚊虫病而产生的，一种 细胞程序性死亡，细胞裂解，分泌带有炎性蛋白的DNA。 少量的Net被认为有助于捕获感染，但过度激活的中性粒细胞会产生 由于物理阻断而导致大量缺氧和免疫血栓的Net 肺泡和微血管构筑。因此，净降级疗法将是一个重大的进步。 在ARDS的治疗中。笛卡尔-30是第一个同种异体(即现成的)工程化人类 骨髓间充质干细胞(MSC)联合分泌两种有效的网络降解药物 酵素。在这个阶段1/2a的研究中，要检验的假设是笛卡尔-30会很好 对中到重度ARDS和COVID患者的耐受性和有效性的证据- 19.目的是确定最大耐受量和初步疗效的证据， 定义疾病的药代动力学特性和生物相关性，并建立有效的 用于后期临床开发的效力分析。这些数据将为设计一款 中重度急性呼吸窘迫综合征患者的对照登记研究。

ABSTRACT This application is to support a clinical trial of the first mRNA engineered cell therapy for Acute Respiratory Distress Syndrome (ARDS), including ARDS caused by COVID-19. The FDA has already reviewed the IND application and determined that the study may proceed. ARDS is a severe inflammatory respiratory failure that kills an estimated 80,000 Americans each year. 80% of ARDS patients require mechanical ventilation. No FDA-approved therapies for ARDS are available. ARDS may result from infectious or non-infectious (e.g., traumatic or chemical) insults. COVID-19 is currently the most common cause of ARDS, and the vast majority of COVID-19 deaths are due to ARDS. Neutrophil Extracellular Traps (NETs) drive the hyperactive inflammatory response in ARDS and COVID-19, and presence of NETs correlates strongly with ARDS severity. NETs are produced by locally-trafficked neutrophils undergoing NETosis, a programmed cell death where the cells lyse to secrete DNA decorated with inflammatory proteins. Low amounts of NETs are thought to help entrap infection, but hyperactivated neutrophils produce large quantities of NETs that cause hypoxia and immune thrombi due to physical blockade of alveoli and microvasculature. A NET-degrading therapy therefore would be a significant advance in treatment of ARDS. Descartes-30 is the first allogeneic (i.e., off-the-shelf) engineered human Mesenchymal Stem Cell (MSC) therapy secreting a combination of two potent NET-degrading enzymes. In this Phase 1/2a study, the hypothesis to be tested is that Descartes-30 will be well tolerated and show evidence of efficacy in patients with moderate to severe ARDS and COVID- 19. Aims are to determine the maximum tolerated dose and evidence of preliminary efficacy, define pharmacokinetic properties and biologic correlates of disease, and establish a validated Potency assay for use in later-stage clinical development. These data will inform the design of a controlled registration study in patients with moderate-to-severe ARDS.