TY - JOUR
T1 - Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles
AU - Gimona, Mario
AU - Brizzi, Maria Felice
AU - Choo, Andre Boon Hwa
AU - Dominici, Massimo
AU - Davidson, Sean M.
AU - Grillari, Johannes
AU - Hermann, Dirk M.
AU - Hill, Andrew F.
AU - de Kleijn, Dominique
AU - Lai, Ruenn Chai
AU - Lai, Charles P.
AU - Lim, Rebecca
AU - Monguió-Tortajada, Marta
AU - Muraca, Maurizio
AU - Ochiya, Takahiro
AU - Ortiz, Luis A.
AU - Toh, Wei Seong
AU - Yi, Yong Weon
AU - Witwer, Kenneth W.
AU - Giebel, Bernd
AU - Lim, Sai Kiang
N1 - Funding Information:
JG is supported by the Christian Doppler Research Association within the Christian Doppler Laboratory on Biotechnology of Skin Aging as well as the Austrian Federal Ministry of Digital and Economic Affairs and the National Foundation for Research, Technology and Development. SMD acknowledges the support of the National Institute for Health Research University College London Hospitals Biomedical Research Centre (BRC233/CM/SD/101320) and the British Heart Foundation (PG/18/44/33790). KWW acknowledges support from the US National Institutes of Health (DA040385, DA047807, AI144997, MH118164, UG3CA241694). CPL received funding from the Academia Sinica Innovative Materials and Analysis Technology Exploration Program (ASiMATE-107-33). KWW has received research funding from the National Institutes of Health (DA040385, DA047807, AI144997, MH118164, UG3CA241694, AG057430), the Michael J. Fox Foundation and AgriSciX Inc. DMH and BG received funding from ERA-NET EuroTransBio. BG also received funding from LeitmarktAgentur.NRW, the European Regional Development Fund 2014–2020 and the European Commission Horizon 2020 project Extracellular Vesicles Promoted Regenerative Osseointegration (H2020-NMBP-TR-IND-2018). ABHC, RCL, WST and SKL are supported by the Agency for Science, Technology and Research under its Health and Biomedical Sciences Industry Alignment Fund Pre-Positioning (award no. H19H610026). MD is supported by ASEOP (Associazione Ematologia e Oncologia Pediatrica. MG is supported by Land Salzburg/IWB/EFRE 2014-2020 P1812596 “EV-TT” and by Land Salzburg/WISS 20125 20102-F1900731-KZP “EV-TT-Bpro,” and by the Government of Salzburg State under the WISS2025 Strategy - Project ID “ExtraNeu.”
Funding Information:
JG is supported by the Christian Doppler Research Association within the Christian Doppler Laboratory on Biotechnology of Skin Aging as well as the Austrian Federal Ministry of Digital and Economic Affairs and the National Foundation for Research, Technology and Development. SMD acknowledges the support of the National Institute for Health Research University College London Hospitals Biomedical Research Centre (BRC233/CM/SD/101320) and the British Heart Foundation (PG/18/44/33790). KWW acknowledges support from the US National Institutes of Health (DA040385, DA047807, AI144997, MH118164, UG3CA241694). CPL received funding from the Academia Sinica Innovative Materials and Analysis Technology Exploration Program (ASiMATE-107-33). KWW has received research funding from the National Institutes of Health (DA040385, DA047807, AI144997, MH118164, UG3CA241694, AG057430), the Michael J. Fox Foundation and AgriSciX Inc. DMH and BG received funding from ERA-NET EuroTransBio. BG also received funding from LeitmarktAgentur.NRW, the European Regional Development Fund 2014?2020 and the European Commission Horizon 2020 project Extracellular Vesicles Promoted Regenerative Osseointegration (H2020-NMBP-TR-IND-2018). ABHC, RCL, WST and SKL are supported by the Agency for Science, Technology and Research under its Health and Biomedical Sciences Industry Alignment Fund Pre-Positioning (award no. H19H610026). MD is supported by ASEOP (Associazione Ematologia e Oncologia Pediatrica. MG is supported by Land Salzburg/IWB/EFRE 2014-2020 P1812596 ?EV-TT? and by Land Salzburg/WISS 20125 20102-F1900731-KZP ?EV-TT-Bpro,? and by the Government of Salzburg State under the WISS2025 Strategy - Project ID ?ExtraNeu.?, MG has a consulting and advisory role at MDimune. JG is co-founder and scientific advisor of Evercyte GmbH. YWY is co-founder, shareholder and employee of ExoCoBio Inc. KWW has a consulting role at MycoMed Technologies, Mosaic Ventures, Guidepoint and NeuroTrauma Sciences. BG is a scientific advisory board member of Evox Therapeutics and Innovex Therapeutics SL. SKL is the founder of Paracrine Therapeutics and has a scientific advisory role at Ilias Biologics and ExoCoBio Inc. All authors participated in the ISCT/ISEV/SOCRATES workshop and discussed the content. BG and SKL drafted the manuscript with support from MG and KWW. All authors approved the manuscript.
Publisher Copyright:
© 2021 International Society for Cell & Gene Therapy
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - MSC-EVs intervention
KW - exosomes
KW - extracellular vesicles
KW - mesenchymal stromal cells
KW - mesencyhmal stem cells
KW - microvesicles
UR - http://www.scopus.com/inward/record.url?scp=85104918473&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104918473&partnerID=8YFLogxK
U2 - 10.1016/j.jcyt.2021.01.001
DO - 10.1016/j.jcyt.2021.01.001
M3 - Article
C2 - 33934807
AN - SCOPUS:85104918473
VL - 23
SP - 373
EP - 380
JO - Cytotherapy
JF - Cytotherapy
SN - 1465-3249
IS - 5
ER -