Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles |
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| Authors: | Mario Gimona Maria Felice Brizzi Andre Boon Hwa Choo Massimo Dominici Sean M. Davidson Johannes Grillari Dirk M. Hermann Andrew F. Hill Dominique de Kleijn Ruenn Chai Lai Charles P. Lai Rebecca Lim Marta Monguió-Tortajada Maurizio Muraca Takahiro Ochiya Luis A. Ortiz Wei Seong Toh Yong Weon Yi Sai Kiang Lim |
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| Affiliation: | 1. Good Manufacturing Practice Laboratory, Spinal Cord Injury and Tissue Regeneration Center Salzburg and Research Program Nanovesicular Therapies, Paracelsus Medical University, Salzburg, Austria;2. Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Torino, Italy;3. Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore, Singapore;4. Technopole Mario Veronesi, Mirandola, Italy;5. Division of Medical Oncology, Laboratory of Cellular Therapy, University of Modena and Reggio Emilia, Modena, Italy;6. The Hatter Cardiovascular Institute, University College London, London, UK;7. Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria;8. Department of Biotechnology, Christian Doppler Laboratory on Biotechnology of Skin Aging, Institute for Molecular Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria;9. Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;10. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia;11. Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, the Netherlands;12. Institute of Medical Biology and Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore;13. Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan;14. Department of Obstetrics and Gynecology, The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Victoria, Australia;15. ICREC Research Program and REMAR-IVECAT group, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, and Cardiology Service, Germans Trias i Pujol University Hospital, Badalona, Spain;16. Department of Women''s and Children''s Health, University of Padova, Padova, Italy;17. Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, Japan;18. Department of Environmental and Occupational Health, Division of Environmental and Occupational Medicine, Graduate School of Public Health at the University of Pittsburgh, Pittsburgh, Pennsylvania, USA;19. Faculty of Dentistry, National University of Singapore, Singapore, Singapore;20. Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore;21. ExoCoBio Exosome Institute, ExoCoBio Inc., Seoul, Korea;22. Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, USA;23. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;24. Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;25. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore;1. McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA;2. Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA;3. Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA;4. College of Arts and Sciences, Ohio State University, Columbus, Ohio, USA;5. Cellf Bio LLC, Winston-Salem, North Carolina, USA;6. Department of Medicine, Gastroenterology Unit, Giambattista Rossi University Hospital, University Hospital Integrated Trust of Verona, University of Verona, Verona, Italy;1. Microscopy Facility, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria;2. GMP Laboratory, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria;3. University Clinic for Blood Group Serology and Transfusion Medicine, Paracelsus Medical University (PMU), Salzburg, Austria;1. Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany;2. Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg – Hessia, Ulm, Germany;3. Institute of Clinical Dentistry, University of Bergen, Bergen, Norway;4. Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy;5. Section for Haematology, Department of Clinical Science, University of Bergen, Bergen, Norway;6. Department of Medicine, Haukeland University Hospital, Bergen, Norway;7. UMR5273 Centre national de la recherche scientifique (CNRS), UPS, Établissement francais du sang (EFS)-INSERM U1031, STROMAlab, Toulouse, France;8. Établissement francais du sang (EFS) Pyrénées-Méditeranée, Toulouse, France;9. Inserm U957, Laboratory for Pathophysiology of Bone Resorption, Faculty of Medicine, University of Nantes, Nantes, France;1. University of California Davis Stem Cell Program, Sacramento, California, USA;2. University of Wisconsin, Madison, Wisconsin, USA;3. Scripps Research Institute, Jupiter, Florida, USA |
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| Abstract: | ![]()
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. |
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