MSC extracellular vesicles for therapy of ARDS - development of a scalable process for production of the mitochondria enriched EV product
Lead Research Organisation:
Queen's University Belfast
Department Name: Sch of Medicine, Dentistry & Biomed Sci
Abstract
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.
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.
