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

Descartes-30 治疗急性呼吸窘迫综合征的 1/2a 期临床研究

基本信息

批准号：
10258574
负责人：
Charles Andrew Stewart
金额：
$ 99.87万
依托单位：
CARTESIAN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258574
关键词：
Acute Lung Injury Adult Respiratory Distress Syndrome Advanced Development Allogenic American Anti-Inflammatory Agents Apoptosis Biological Biological Assay Blood Bronchoalveolar Lavage COVID-19 COVID-19 mortality COVID-19 patient Cell Death Cell Therapy Cells Chemicals Clinical Clinical Research Clinical Trials Cyclic GMP DNA Data Deoxyribonucleases Disease Dose Dose-Limiting Drug Kinetics Eligibility Determination Engineering Enzymes FDA approved Fluorometry Gene Expression Histone H3 Hour Human Engineering Hyperactivity Hypoxia Immune Immunophenotyping Infection Inflammation Mediators Inflammatory Inflammatory Response Infusion procedures Internet Kidney Length of Stay Letters Lung Maps Maximum Tolerated Dose Measures Mechanical ventilation Mesenchymal Stem Cells Messenger RNA Modeling Mus Patients Peroxidases Phase Positioning Attribute Production Property Proteins RNA Respiratory Failure Risk Safety Sampling Severities Small Business Innovation Research Grant Specificity Testing Therapy trial Thrombus Time Toxic effect Vasoconstrictor Agents Work cell free DNA clinical development clinical lot contagion cytokine design exhaustion extracellular intravenous administration macrophage mortality neutrophil operation pharmacokinetics and pharmacodynamics primary endpoint research and development secondary endpoint single-cell RNA sequencing stem cell therapy trafficking

项目摘要

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.

抽象的该申请旨在支持第一个 mRNA 工程细胞疗法治疗急性疾病的临床试验呼吸窘迫综合征 (ARDS)，包括由 COVID-19 引起的 ARDS。 FDA 有已经审查了 IND 申请并确定可以继续进行研究。 ARDS 是一种据估计，严重的炎症性呼吸衰竭每年夺去 80,000 名美国人的生命。 80% 的 ARDS 患者需要机械通气。目前尚无 FDA 批准的 ARDS 治疗方法可用的。 ARDS 可能由感染性或非感染性（例如创伤性或化学性）损伤引起。 COVID-19 目前是 ARDS 的最常见原因，并且绝大多数 COVID-19 死亡是由于 ARDS 造成的。中性粒细胞胞外陷阱 (NET) 导致过度活跃 ARDS 和 COVID-19 中的炎症反应以及 NET 的存在与 ARDS 严重程度。 NET 是由局部运输的中性粒细胞产生的，该粒细胞正在经历 NETosis，这是一种程序性细胞死亡，细胞裂解并分泌带有炎症蛋白的 DNA。人们认为少量的 NET 有助于捕获感染，但过度活跃的中性粒细胞会产生大量的NET由于物理封锁而导致缺氧和免疫血栓肺泡和微血管。因此，NET 降解疗法将是一个重大进步治疗ARDS。 Descartes-30 是第一个同种异体（即现成的）工程人类间充质干细胞 (MSC) 疗法分泌两种有效的 NET 降解组合酶。在这项 1/2a 期研究中，要测试的假设是 Descartes-30 将很好地发挥作用对中度至重度 ARDS 和 COVID 患者具有耐受性并显示出疗效的证据 19. 目的是确定最大耐受剂量和初步疗效的证据，定义疾病的药代动力学特性和生物学相关性，并建立经过验证的用于后期临床开发的效力测定。这些数据将为设计提供信息中度至重度 ARDS 患者的对照登记研究。