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无效药理治疗的重症患者死亡率的主要原因。研究间充质基质细胞（MSC）正在研究作为ARDS的细胞疗法，包括与COVID-19相关的ARDS。临床研究统一证明了安全性，最近一些研究表明有意义和有意义的功效。细胞外囊泡是MSC分泌组的关键组成部分，包括我们自己的研究越来越多的研究表明，EV在ARDS的临床前模型中概括了MSC的作用。我们已经确定线粒体转移是EV免疫调节，抗菌，修复效应和肺泡毛细管完整性的改善的中心，因此针对ARDS发病机理的所有关键方面。电动汽车进一步临床开发的主要障碍是成本效益的临床等级EV的大规模生产。本项目的主要目标是使用临床级MSC和无Zeno的无效试剂开发和优化生物反应器系统中富含线粒体的富含电动汽车的可扩展方法通过这一目标进行操作。实现的过渡将促使下游开发计划在随后的DPFS应用程序中，重点是测试所得EV产品在小型动物模型中的治疗功效，EV生产方案及其转移到C-GMP设施的规模。该产品的最终用户是ARDS患者和ICU临床医生。目前尚无有效的ARDS治疗。因此，该治疗剂旨在解决未满足的临床需求的领域。尽管该项目集中在ARDS上，但数据将与其他肺部疾病有关，例如COPD，IPF，支气管扩张和炎症状况，例如脓毒症，在脓毒症中，炎症和线粒体功能障碍是病原体的重要方面。