MSC extracellular vesicles for therapy of ARDS - development of a scalable process for production of the mitochondria enriched EV product

用于治疗 ARDS 的 MSC 细胞外囊泡 - 开发生产富含线粒体的 EV 产品的可扩展工艺

• 批准号: MR/Z503691/1
• 负责人: Anna Krasnodembskaya
• 金额: $ 31.47万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FZ503691%2F1
• 关键词: MSC; extracellular; vesicles; therapy; ARDS

Acute Respiratory Distress Syndrome is a major cause of mortality in the critically ill patients with no effective pharmacological treatment. Mesenchymal stromal cells (MSCs) are being investigated as a cell therapy for ARDS including that associated with COVID-19. Clinical investigations have uniformly demonstrated safety with some recent investigations demonstrating significant and clinically meaningful efficacy. Extracellular vesicles are key components of MSC secretome, and growing number of studies including our own demonstrate that EVs recapitulate effects of MSCs in the preclinical models of ARDS. We have identified mitochondrial transfer to be central for EV immunomodulatory, antimicrobial, reparative effects and improvement in the alveolar-capillary integrity- thus targeting all key aspects of ARDS pathogenesis. The main obstacle for further clinical development of EVs is cost effective large scale production of clinical grade EVs.The main objective of the present project is to develop and optimise a scalable method of production of the mitochondria-enriched EVs in the bioreactor system using clinical grade MSCs and zeno-free reagents, which will be readily amenable to large scale GMP production whilst demonstrating therapeutic usefulness and established mechanism of action.Successful transition through this objective will prompt downstream development plans in subsequent DPFS application focused on the testing of the therapeutic efficacy of the resultant EV product in the small and large animal models, scale up of the EV production protocol and its transfer to the c-GMP facility.The end users of this product are ARDS patients and the ICU clinicians. Currently there is no effective treatment for ARDS; this therapeutic agent therefore aims to address an area of unmet clinical need. While this project is focused on ARDS, the data will be relevant to other lung conditions such as COPD, IPF, broncheactasis and inflammatory conditions such as sepsis where dysregulated inflammation and mitochondrial dysfunction are important aspects of pathogenesis.

急性呼吸窘迫综合征是缺乏有效药物治疗的危重患者死亡的主要原因。间充质基质细胞 (MSC) 正在研究作为 ARDS 的细胞疗法，包括与 COVID-19 相关的 ARDS。临床研究一致证明了安全性，最近的一些研究显示了显着且具有临床意义的功效。细胞外囊泡是 MSC 分泌组的关键组成部分，越来越多的研究（包括我们自己的研究）表明，EV 重现了 MSC 在 ARDS 临床前模型中的作用。我们已经确定线粒体转移是 EV 免疫调节、抗菌、修复作用和改善肺泡毛细血管完整性的核心，从而针对 ARDS 发病机制的所有关键方面。 EV 进一步临床开发的主要障碍是临床级 EV 的成本效益大规模生产。本项目的主要目标是开发和优化使用临床级生物反应器系统中生产富含线粒体的 EV 的可扩展方法MSC 和无芝诺试剂，将很容易进行大规模 GMP 生产，同时展示治疗用途和既定的作用机制。通过这一目标的成功过渡将促进后续 DPFS 应用中的下游开发计划，重点是测试由此产生的 EV 产品在小型和大型动物模型中的治疗效果，扩大 EV 生产方案并将其转移到 c-GMP 设施。该产品的最终用户是 ARDS 患者和 ICU 临床医生。目前ARDS尚无有效治疗方法；因此，该治疗剂旨在解决临床需求未得到满足的领域。虽然该项目的重点是急性呼吸窘迫综合征，但这些数据也与其他肺部疾病有关，如慢性阻塞性肺病、特发性肺纤维化、支气管扩张和脓毒症等炎症性疾病，其中炎症失调和线粒体功能障碍是发病机制的重要方面。