Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles
Autor: | Massimo Dominici, Takahiro Ochiya, Rebecca Lim, Bernd Giebel, Andre Choo, Wei Seong Toh, Maria Felice Brizzi, Yong Weon Yi, Dominique P.V. de Kleijn, Johannes Grillari, Charles P. Lai, Dirk M. Hermann, Andrew F. Hill, Mario Gimona, Maurizio Muraca, Sean M. Davidson, Kenneth W. Witwer, Luis A. Ortiz, Ruenn Chai Lai, Marta Monguió-Tortajada, Sai Kiang Lim |
---|---|
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Drug Cancer Research mesencyhmal stem cells Stromal cell media_common.quotation_subject Immunology Medizin Graft vs Host Disease MSC-EVs intervention exosomes Bioinformatics 03 medical and health sciences Paracrine signalling 0302 clinical medicine Humans Immunology and Allergy Medicine Potency Prospective Studies Genetics (clinical) media_common extracellular vesicles mesenchymal stromal cells microvesicles Transplantation business.industry Mesenchymal stem cell Mesenchymal Stem Cells Biological activity Cell Biology respiratory system Microvesicles 030104 developmental biology Oncology 030220 oncology & carcinogenesis Stem cell business |
Zdroj: | Cytotherapy r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol instname |
ISSN: | 1465-3249 |
Popis: | Mesenchymal stromal/stem cells (MSCs) have been widely tested against many diseases, with more than 1000 registered clinical trials worldwide. Despite many setbacks, MSCs have been approved for the treatment of graft-versus-host disease and Crohn disease. However, it is increasingly clear that MSCs exert their therapeutic functions in a paracrine manner through the secretion of small extracellular vesicles (sEVs) of 50-200 nm in diameter. Unlike living cells that can persist long-term, sEVs are non-living and non-replicative and have a transient presence in the body. Their small size also renders sEV preparations highly amenable to sterilization by filtration. Together, acellular MSC-sEV preparations are potentially safer and easier to translate into the clinic than cellular MSC products. Nevertheless, there are inherent challenges in the development of MSC-sEV drug products. MSC-sEVs are products of living cells, and living cells are sensitive to changes in the external microenvironment. Consequently, quality control metrics to measure key identity and potency features of MSC-sEV preparations have to be specified during development of MSC-sEV therapeutics. The authors have previously described quantifiable assays to define the identity of MSC-sEVs. Here the authors discuss requirements for prospective potency assays to predict the therapeutic effectiveness of the drug substance in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Although potency assays should ideally reflect the mechanism of action (MoA), this is challenging because the MoA for the reported efficacy of MSC-sEV preparations against multiple diseases of diverse underlying pathology is likely to be complex and different for each disease and difficult to fully elucidate. Nevertheless, robust potency assays could be developed by identifying the EV attribute most relevant to the intended biological activity in EV-mediated therapy and quantifying the EV attribute. Specifically, the authors highlight challenges and mitigation measures to enhance the manufacture of consistent and reproducibly potent sEV preparations, to identify and select the appropriate EV attribute for potency assays despite a complex "work-in-progress" MoA and to develop assays likely to be compliant with regulatory guidance for assay validation. (C) 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved. |
Databáze: | OpenAIRE |
Externí odkaz: |