Advertisement

International Society for Extracellular Vesicles and International Society for Cell and Gene Therapy statement on extracellular vesicles from mesenchymal stromal cells and other cells: considerations for potential therapeutic agents to suppress coronavirus disease-19

      STATEMENT: The International Society for Cellular and Gene Therapies (ISCT) and the International Society for Extracellular Vesicles (ISEV) recognize the potential of extracellular vesicles (EVs, including exosomes) from mesenchymal stromal cells (MSCs) and possibly other cell sources as treatments for COVID-19. Research and trials in this area are encouraged. However, ISEV and ISCT do not currently endorse the use of EVs or exosomes for any purpose in COVID-19, including but not limited to reducing cytokine storm, exerting regenerative effects or delivering drugs, pending the generation of appropriate manufacturing and quality control provisions, pre-clinical safety and efficacy data, rational clinical trial design and proper regulatory oversight.
      First described in December 2019, the severe acute respiratory syndrome associated with coronavirus disease-19 (COVID-19) quickly evolved into a pandemic, with severe and increasing worldwide morbidity and mortality. Although most infected patients have mild to moderate symptoms or are even asymptomatic, older patients and those with pre-existing chronic diseases are at greater risk of developing serious complications, such as pneumonia or multiple organ failure. COVID-19 respiratory infection is marked by dysregulated immune responses leading to significant respiratory pathology as well as increased probabilities for multi-organ pathologies. While the inflammatory pathways are still being elucidated, notable components include increased circulating levels of pro-inflammatory cytokines and other mediators, including interleukin-6 (IL-6), interleukin-1β (IL-1β), induced protein 10 (IP10) and monocyte chemoattractant protein-1 (MCP-1) [
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • Wang T.
      • Zhang X.
      • Chen H.
      • Yu H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Diao B.
      • Wang C.
      • Tan Y.
      • Chen X.
      • Liu Y.
      • Ning L.
      • Chen L.
      • Li M.
      • Liu Y.
      • Wang G.
      • et al.
      Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19).
      ,
      • Yang Y.
      • Shen C.
      • Li J.
      • Yuan J.
      • Yang M.
      • Wang F.
      • Li G.
      • Li Y.
      • Xing L.
      • Peng L.
      • et al.
      Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome.
      ]. There are also significant alterations in circulating inflammatory cell populations, with initial lymphocytosis followed by severe lymphopenia, with increased ratios of helper to regulatory T cells [
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • Wang T.
      • Zhang X.
      • Chen H.
      • Yu H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Diao B.
      • Wang C.
      • Tan Y.
      • Chen X.
      • Liu Y.
      • Ning L.
      • Chen L.
      • Li M.
      • Liu Y.
      • Wang G.
      • et al.
      Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19).
      ,
      • Qin C.
      • Zhou L.
      • Hu Z.
      • Zhang S.
      • Yang S.
      • Tao Y.
      • Xie C.
      • Ma K.
      • Shang K.
      • Wang W.
      • et al.
      Dysregulation of immune response in patients with COVID-19 in Wuhan, China.
      ]. Since dysregulated immune responses and the cytokine storm are triggers for development of acute respiratory distress syndrome, an increasing effort and current clinical trials are focused on immune therapeutic approaches, such as IL-1 blockade (anakinra), IL-6 receptor blockade (tocilizumab) and Janus kinase inhibition [
      • Mehta P.
      • McAuley D.F.
      • Brown M.
      • Sanchez E.
      • Tattersall R.S.
      • Manson J.J.
      Hlh Across Speciality Collaboration, U.K
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      ]. In parallel, there are a rapidly increasing number of cell-based therapy investigations, mostly utilizing mesenchymal stromal cells (MSCs) [
      • Khoury M.
      • Cuenca J.
      • Cruz F.F.
      • Figueroa F.E.
      • Rocco P.R.M.
      • Weiss D.J.
      Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19.
      ]. These are based on supporting pre-clinical data for use of MSCs delivered either systemically or intratracheally in pre-clinical models of acute lung injuries and on demonstration of safety of systemic MSC administration in recent trials for acute respiratory distress syndrome resulting from other etiologies [
      • Laffey J.G.
      • Matthay M.A.
      Fifty Years of Research in ARDS. Cell-based therapy for acute respiratory distress syndrome. Biology and potential therapeutic value.
      ,
      • Matthay M.A.
      • Calfee C.S.
      • Zhuo H.
      • Thompson B.T.
      • Wilson J.G.
      • Levitt J.E.
      • Rogers A.J.
      • Gotts J.E.
      • Wiener-Kronish J.P.
      • Bajwa E.K.
      • et al.
      Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.
      ].
      Among the cell-based therapy investigations for COVID-19, some registered clinical trials aim to utilize extracellular vesicles (EVs) prepared from MSC-conditioned media rather than the cells themselves. MSC-EVs will be administered intravenously (ChiCTR2000030484) or by inhalation (NCT04276987, ChiCTR2000030261). The rationale for these approaches is based on a relatively small but growing number of investigations in pre-clinical lung injury and sepsis models in which MSC-EV preparations were described as being as safe and effective as—if not more than—their parent cells [
      • Mahida R.Y.
      • Matsumoto S.
      • Matthay M.A.
      Extracellular vesicles: a new frontier for research in acute respiratory distress syndrome.
      ,
      • Worthington E.N.
      • Hagood J.S.
      Therapeutic use of extracellular vesicles for acute and chronic lung disease.
      ]. The approach is further supported by a growing body of literature on the therapeutic potential and mechanisms of EVs in a wide range of diseases, including recent positive results in a steroid-refractory graft-versus-host disease patient treated with MSC-EVs and in a single-center, randomized, placebo-controlled phase 2/3 clinical pilot study on chronic kidney disease patients treated with MSC-EVs [
      • Kordelas L.
      • Rebmann V.
      • Ludwig A.K.
      • Radtke S.
      • Ruesing J.
      • Doeppner T.R.
      • Epple M.
      • Horn P.A.
      • Beelen D.W.
      • Giebel B.
      MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease.
      ,
      • Nassar W.
      • El-Ansary M.
      • Sabry D.
      • Mostafa M.A.
      • Fayad T.
      • Kotb E.
      • Temraz M.
      • Saad A.N.
      • Essa W.
      • Adel H.
      Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases.
      ].
      The mechanisms by which EVs exert their beneficial effects, as well as their site(s) of action, remain incompletely understood. Nonetheless, effects observed in a range of pre-clinical non-COVID-19 model systems suggest that they may also have efficacy against COVID-19. For example, systemic administration of MSC-EV preparations modulated immune responses such as elevated cytokine storms in relevant lung disease models, including acute lung injury and sepsis [
      • Liu J.
      • Chen T.
      • Lei P.
      • Tang X.
      • Huang P.
      Exosomes released by bone marrow mesenchymal stem cells attenuate lung injury induced by intestinal ischemia reperfusion via the TLR4/NF-kappaB pathway.
      ,
      • Mansouri N.
      • Willis G.R.
      • Fernandez-Gonzalez A.
      • Reis M.
      • Nassiri S.
      • Mitsialis S.A.
      • Kourembanas S.
      Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes.
      ,
      • Monsel A.
      • Zhu Y.G.
      • Gennai S.
      • Hao Q.
      • Hu S.
      • Rouby J.J.
      • Rosenzwajg M.
      • Matthay M.A.
      • Lee J.W.
      Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice.
      ,
      • Morrison T.J.
      • Jackson M.V.
      • Cunningham E.K.
      • Kissenpfennig A.
      • McAuley D.F.
      • O'Kane C.M.
      • Krasnodembskaya A.D.
      Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer.
      ,
      • Park K.S.
      • Svennerholm K.
      • Shelke G.V.
      • Bandeira E.
      • Lasser C.
      • Jang S.C.
      • Chandode R.
      • Gribonika I.
      • Lotvall J.
      Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10.
      ,
      • Varkouhi A.K.
      • Jerkic M.
      • Ormesher L.
      • Gagnon S.
      • Goyal S.
      • Rabani R.
      • Masterson C.
      • Spring C.
      • Chen P.Z.
      • Gu F.X.
      • et al.
      Extracellular vesicles from interferon-gamma-primed human umbilical cord mesenchymal stromal cells reduce Escherichia coli-induced acute lung injury in rats.
      ,
      • Willis G.R.
      • Fernandez-Gonzalez A.
      • Anastas J.
      • Vitali S.H.
      • Liu X.
      • Ericsson M.
      • Kwong A.
      • Mitsialis S.A.
      • Kourembanas S.
      Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation.
      ,
      • Zhu Y.G.
      • Feng X.M.
      • Abbott J.
      • Fang X.H.
      • Hao Q.
      • Monsel A.
      • Qu J.M.
      • Matthay M.A.
      • Lee J.W.
      Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice.
      ]. Notably, in Escherichia coli-induced pneumonia mouse models, MSC-EV administration was found to enhance phagocytosis of bacteria [
      • Hao Q.
      • Gudapati V.
      • Monsel A.
      • Park J.H.
      • Hu S.
      • Kato H.
      • Lee J.H.
      • Zhou L.
      • He H.
      • Lee J.W.
      Mesenchymal stem cell-derived extracellular vesicles decrease lung injury in mice.
      ,
      • Monsel A.
      • Zhu Y.G.
      • Gennai S.
      • Hao Q.
      • Hu S.
      • Rouby J.J.
      • Rosenzwajg M.
      • Matthay M.A.
      • Lee J.W.
      Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice.
      ]. In a pig model, MSC-EVs were shown to attenuate influenza virus-induced acute lung injury, among other conditions, by inhibiting influenza virus replication [
      • Khatri M.
      • Richardson L.A.
      • Meulia T.
      Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.
      ]. Disease-attenuating effects on inflammatory immune responses following MSC-EV administration have also been observed in other disease models [
      • Börger V.
      • Bremer M.
      • Ferrer-Tur R.
      • Gockeln L.
      • Stambouli O.
      • Becic A.
      • Giebel B.
      Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents.
      ]. In an ischemic stroke model, for example, syste mic MSC-EV administration reduced stroke-induced lymphopenia and pro-inflammatory immune responses in the brain and periphery, resulting in overall improvement of disease symptoms [
      • Doeppner T.R.
      • Herz J.
      • Gorgens A.
      • Schlechter J.
      • Ludwig A.K.
      • Radtke S.
      • de Miroschedji K.
      • Horn P.A.
      • Giebel B.
      • Hermann D.M.
      Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression.
      ,
      • Wang C.
      • Börger V.
      • Sardari M.
      • Murke F.
      • Skuljec J.
      • Pul R.
      • Hagemann N.
      • Dzyubenko E.
      • Dittrich R.
      • Gregorius J.
      • et al.
      Mesenchymal stromal cell-derived small extracellular vesicles induce ischemic neuroprotection by modulating leukocytes and specifically neutrophils.
      ]. These preliminary observations support MSC-EV administration as a potential treatment option for COVID-19.
      However, the specific scientific rationale for the administration of MSC-EV and other EV treatments in COVID-19 patients needs to be better understood and justified. For example, MSC-EVs do not necessarily suppress immune responses, but rather modulate them. Specifically, they seem to moderate acute immune responses toward regulatory responses, with the latter inducing tolerance and restoring homeostasis [
      • Giebel B.
      • Hermann D.M.
      Identification of the right cell sources for the production of therapeutically active extracellular vesicles in ischemic stroke.
      ,
      • Zhang B.
      • Yeo R.W.Y.
      • Lai R.C.
      • Sim E.W.K.
      • Chin K.C.
      • Lim S.K.
      Mesenchymal stromal cell exosome–enhanced regulatory T-cell production through an antigen-presenting cell–mediated pathway.
      ,
      • Zhang B.
      • Yin Y.
      • Lai R.C.
      • Tan S.S.
      • Choo A.B.H.
      • Lim S.K.
      Mesenchymal Stem Cells Secrete Immunologically Active Exosomes.
      ]. While tolerance induction in graft-versus-host disease and other non-infectious diseases may be beneficial, it might also have severe adverse effects in the presence of replicating pathogens. Although influenza and E. coli infections were attenuated in selected models [
      • Hao Q.
      • Gudapati V.
      • Monsel A.
      • Park J.H.
      • Hu S.
      • Kato H.
      • Lee J.H.
      • Zhou L.
      • He H.
      • Lee J.W.
      Mesenchymal stem cell-derived extracellular vesicles decrease lung injury in mice.
      ,
      • Khatri M.
      • Richardson L.A.
      • Meulia T.
      Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.
      ,
      • Monsel A.
      • Zhu Y.G.
      • Gennai S.
      • Hao Q.
      • Hu S.
      • Rouby J.J.
      • Rosenzwajg M.
      • Matthay M.A.
      • Lee J.W.
      Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice.
      ], other viruses and bacteria might conceivably expand in an uncontrolled manner in induced tolerogenic environments.
      A number of additional issues should be considered before administering MSC-EVs to COVID-19 patients. These include the source of MSC-EVs. MSCs are a heterogeneous cell entity that can be obtained from different tissues. Even if derived from the same tissues, they may display interindividual and possibly clone-specific functional differences [
      • Phinney D.G.
      Functional heterogeneity of mesenchymal stem cells: implications for cell therapy.
      ,
      • Phinney D.G.
      • Kopen G.
      • Righter W.
      • Webster S.
      • Tremain N.
      • Prockop D.J.
      Donor variation in the growth properties and osteogenic potential of human marrow stromal cells.
      ,
      • Radtke S.
      • Gorgens A.
      • Liu B.
      • Horn P.A.
      • Giebel B.
      Human mesenchymal and murine stromal cells support human lympho-myeloid progenitor expansion but not maintenance of multipotent haematopoietic stem and progenitor cells.
      ,
      • Vogel W.
      • Grunebach F.
      • Messam C.A.
      • Kanz L.
      • Brugger W.
      • Buhring H.J.
      Heterogeneity among human bone marrow-derived mesenchymal stem cells and neural progenitor cells.
      ]. Indeed, side-by-side comparison of four MSC-EV preparations harvested from the conditioned media of different donor-derived bone marrow MSCs demonstrated significant variations in cytokine content [
      • Kordelas L.
      • Rebmann V.
      • Ludwig A.K.
      • Radtke S.
      • Ruesing J.
      • Doeppner T.R.
      • Epple M.
      • Horn P.A.
      • Beelen D.W.
      • Giebel B.
      MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease.
      ]. Whether this correlates with therapeutic potency is not yet clear; however, in the example of the ischemic stroke model, it was demonstrated that MSC-EV preparations with comparable particle and protein contents can significantly differ in potency. While some preparations effectively suppressed stroke symptoms, others failed to exert therapeutic activities [
      • Wang C.
      • Börger V.
      • Sardari M.
      • Murke F.
      • Skuljec J.
      • Pul R.
      • Hagemann N.
      • Dzyubenko E.
      • Dittrich R.
      • Gregorius J.
      • et al.
      Mesenchymal stromal cell-derived small extracellular vesicles induce ischemic neuroprotection by modulating leukocytes and specifically neutrophils.
      ]. Furthermore, in an acute lung injury model, EVs from young, but not aged, MSCs alleviated lipopolysaccharide-induced acute lung injury [
      • Huang R.
      • Qin C.
      • Wang J.
      • Hu Y.
      • Zheng G.
      • Qiu G.
      • Ge M.
      • Tao H.
      • Shu Q.
      • Xu J.
      Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury.
      ].
      Potentially, heterogeneity of EV potency due to different sources, preparations, aging and other factors could be resolved by generating immortalized clonal MSC lines that could be rigorously tested for EV production and potency [
      • Chen T.S.
      • Arslan F.
      • Yin Y.
      • Tan S.S.
      • Lai R.C.
      • Choo A.B.
      • Padmanabhan J.
      • Lee C.N.
      • de Kleijn D.P.
      • Lim S.K.
      Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs.
      ]. Still, apart from their immunomodulatory capabilities, MSC-EVs apparently also control additional biological processes, some with approved therapeutic functions [
      • Arslan F.
      • Lai R.C.
      • Smeets M.B.
      • Akeroyd L.
      • Choo A.
      • Aguor E.N.
      • Timmers L.
      • van Rijen H.V.
      • Doevendans P.A.
      • Pasterkamp G.
      • et al.
      Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury.
      ] and others that might trigger unforeseen side effects. Just recently, it was found that adipose-derived MSC-EVs had higher thrombogenic activity than bone marrow-derived MSC-EVs [
      • Chance T.C.
      • Rathbone C.R.
      • Kamucheka R.M.
      • Peltier G.C.
      • Cap A.P.
      • Bynum J.A.
      The effects of cell type and culture condition on the procoagulant activity of human mesenchymal stromal cell-derived extracellular vesicles.
      ,
      • Silachev D.N.
      • Goryunov K.V.
      • Shpilyuk M.A.
      • Beznoschenko O.S.
      • Morozova N.Y.
      • Kraevaya E.E.
      • Popkov V.A.
      • Pevzner I.B.
      • Zorova L.D.
      • Evtushenko E.A.
      • et al.
      Effect of MSCs and MSC-derived extracellular vesicles on human blood coagulation.
      ]. Thus, the source of parental cells might increase thrombosis risk. Coupled with the finding that activation of complement pathways and an associated procoagulant state seem to result in catastrophic microvascular injury syndrome in a proportion of severe COVID-19 cases [
      • Magro C.
      • Mulvey J.J.
      • Berlin D.
      • Nuovo G.
      • Salvatore S.
      • Harp J.
      • Baxter-Stoltzfus A.
      • Laurence J.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      ], MSC-EV administration could even be counterproductive in COVID-19.
      To this end, it is imperative that stringent “identity” and “potency” parameters are defined and potential side effects addressed before MSC-EV or other EV preparations are released for therapeutic applications [
      • Lener T.
      • Gimona M.
      • Aigner L.
      • Borger V.
      • Buzas E.
      • Camussi G.
      • Chaput N.
      • Chatterjee D.
      • Court F.A.
      • Del Portillo H.A.
      • et al.
      Applying extracellular vesicles based therapeutics in clinical trials—an ISEV position paper.
      ,
      • Reiner A.T.
      • Witwer K.W.
      • van Balkom B.W.M.
      • de Beer J.
      • Brodie C.
      • Corteling R.L.
      • Gabrielsson S.
      • Gimona M.
      • Ibrahim A.G.
      • de Kleijn D.
      • et al.
      Concise review: developing best-practice models for the therapeutic use of extracellular vesicles.
      ,
      • Witwer K.W.
      • Van Balkom B.W.M.
      • Bruno S.
      • Choo A.
      • Dominici M.
      • Gimona M.
      • Hill A.F.
      • De Kleijn D.
      • Koh M.
      • Lai R.C.
      • et al.
      Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications.
      ]. To date, many groups use in-house MSC-EV manufacturing and characterization strategies, mainly for pre-clinical studies [
      • Börger V.
      • Bremer M.
      • Ferrer-Tur R.
      • Gockeln L.
      • Stambouli O.
      • Becic A.
      • Giebel B.
      Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents.
      ]. Protocols fulfilling Good Manufacturing Practice (GMP) criteria are sparse, and just a few have been published [
      • Gimona M.
      • Pachler K.
      • Laner-Plamberger S.
      • Schallmoser K.
      • Rohde E.
      Manufacturing of human extracellular vesicle-based therapeutics for clinical use.
      ,
      • Pachler K.
      • Lener T.
      • Streif D.
      • Dunai Z.A.
      • Desgeorges A.
      • Feichtner M.
      • Oller M.
      • Schallmoser K.
      • Rohde E.
      • Gimona M.
      A Good Manufacturing Practice-grade standard protocol for exclusively human mesenchymal stromal cell-derived extracellular vesicles.
      ,
      • Rohde E.
      • Pachler K.
      • Gimona M.
      Manufacturing and characterization of extracellular vesicles from umbilical cord-derived mesenchymal stromal cells for clinical testing.
      ]. For product candidates, studies focusing on safety and clinical pharmacology need to be performed. Results of such studies are mandatory to provide guidance for adjustment of manufacturing, storage, dosing and administration of EV-based therapeutics in specific target diseases.
      We would like to refer to a recent statement by ISCT on the use of MSCs in COVID-19 [
      • Khoury M.
      • Rocco P.R.M.
      • Phinney D.G.
      • Krampera M.
      • Martin I.
      • Viswanathan S.
      • Nolta J.A.
      • LeBlanc K.
      • Galipeau J.
      • Weiss D.J.
      Cell-based therapies for COVID-19: proper clinical investigations are essential.
      ] and one by the Italian STEMnet, as many of the same considerations apply to MSC-EVs or other EVs. Governmental organizations, health care providers and clinical investigators must take the lead by insisting that clinical uses of EVs follow appropriate scientific, regulatory and ethical guidelines and are approved only after a rigorous review by duly empowered agencies. The ethical guidelines produced by the World Health Organization are a useful baseline
      Organisation WH. Guidance for managing ethical issues in infectious disease outbreaks. World Heal Organ 2016:62.
      2Organisation WH. Guidance for managing ethical issues in infectious disease outbreaks. World Heal Organ 2016:62.
      . The urgency of the current outbreak does not justify administration of EVs in uncontrolled compassionate use settings and does not obviate the need to register clinical trials, obtain informed consent from patients or proxies and otherwise comply with good clinical practice. In particular, even limited compassionate use should employ well-characterized MSC-EV preparations produced through strict GMP conditions under the oversight of the relevant national regulatory entity. Additional outbreak-specific measures may be needed, including establishing simplified clinical protocols for hospitalized patients, such as the World Health Organization COVID-19 core protocol; minimizing risks to trial integrity
      FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic Guidance for Industry, Investigators, and Institutional Review Boards. 2020.
      3FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic Guidance for Industry, Investigators, and Institutional Review Boards. 2020.
      ; and changing logistics of trial participant visits (e.g., implementation of remote assessments) as well as protocol changes for the sake of hazard minimization, which may need to be implemented and reported, in Europe, to the Institute for Research in Biomedicine Barcelona after the fact. Certainly, to foster developments, it is helpful to have regulatory flexibility and support from sources such as the US Food and Drug Administration special emergency program for possible therapies, the Coronavirus Treatment Acceleration Program
      Coronavirus Treatment Acceleration Program (CTAP) | FDA n.d. https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap (accessed April 1, 2020).
      4Coronavirus Treatment Acceleration Program (CTAP) | FDA n.d. https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap (accessed April 1, 2020).
      , the European Medicines Agency (EMA) COVID-19 Pandemic Task Force
      COVID-19 EMA pandemic Task Force (COVID-ETF): “to help EU Member States and the European Commission to take quick and coordinated regulatory action on the development, authorisation and safety monitoring of treatments and vaccines intended for the treatment and prevention of COVID-19.” https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/emas-governance-during-covid-19-pandemic#covid-19-ema-pandemic-task-force-section
      5COVID-19 EMA pandemic Task Force (COVID-ETF): “to help EU Member States and the European Commission to take quick and coordinated regulatory action on the development, authorisation and safety monitoring of treatments and vaccines intended for the treatment and prevention of COVID-19.” https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/emas-governance-during-covid-19-pandemic#covid-19-ema-pandemic-task-force-section
      , the EMA guidance for medicine developers and companies on COVID-19 and the guidelines for clinical trials published by an EMA-coordinated group or the Medicines and Healthcare Products Regulatory Agency, respectively. Most or all of the considerations covered for cell-based therapies are also applicable to EV investigations.
      In conclusion, to mitigate the risk of potentially life-threatening side effects, ISCT and ISEV strongly urge that the potential benefits and risks in the use of MSC-EVs for COVID-19 be weighed carefully against available pre-clinical data in relevant animal models and clinical data from relevant MSC clinical trials and that any use of EVs be carefully evaluated through rational clinical trial design, employing well-characterized EV preparations produced under strict GMP conditions and under the proper regulatory oversight.

      Funding

      No funding was received.

      Declaration of competing interest

      JDA is the co-founder of an exosome therapeutics company called Somos Therapeutics, Inc. BG is a scientific advisory board member with Evox Therapeutics and Innovex Therapeutics SL. MG has a consulting and advisory role with MDimune. BLL has stock and other ownership interests with Tmunity Therapeutics; has received honoraria from Novartis, Terumo and AstraZeneca; and has a consulting or advisory role with Brammer Bio/ThermoFisher Viral Vector Services, Avectas, Immuneel, Ori Biotech and Vycellix. SKL is the founder of Paracrine Therapeutics and has a scientific advisory role with Ilias Biologics and ExoCo. SAM is the inventor of intellectual property licensed by BCH to United Therapeutics Corp.

      Author contributions

      Drafting the manuscript: VB, DJW, KWW, SKL, BG. All authors have approved the final article.

      References

        • Arslan F.
        • Lai R.C.
        • Smeets M.B.
        • Akeroyd L.
        • Choo A.
        • Aguor E.N.
        • Timmers L.
        • van Rijen H.V.
        • Doevendans P.A.
        • Pasterkamp G.
        • et al.
        Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury.
        Stem Cell Res. 2013; 10: 301-312
        • Börger V.
        • Bremer M.
        • Ferrer-Tur R.
        • Gockeln L.
        • Stambouli O.
        • Becic A.
        • Giebel B.
        Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents.
        Int J Mol Sci. 2017; 18
        • Chance T.C.
        • Rathbone C.R.
        • Kamucheka R.M.
        • Peltier G.C.
        • Cap A.P.
        • Bynum J.A.
        The effects of cell type and culture condition on the procoagulant activity of human mesenchymal stromal cell-derived extracellular vesicles.
        J Trauma Acute Care Surg. 2019; 87: S74-S82
        • Chen G.
        • Wu D.
        • Guo W.
        • Cao Y.
        • Huang D.
        • Wang H.
        • Wang T.
        • Zhang X.
        • Chen H.
        • Yu H.
        • et al.
        Clinical and immunological features of severe and moderate coronavirus disease 2019.
        J Clin Invest. 2020; 130
        • Chen T.S.
        • Arslan F.
        • Yin Y.
        • Tan S.S.
        • Lai R.C.
        • Choo A.B.
        • Padmanabhan J.
        • Lee C.N.
        • de Kleijn D.P.
        • Lim S.K.
        Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs.
        J Transl Med. 2011; 9: 47
        • Diao B.
        • Wang C.
        • Tan Y.
        • Chen X.
        • Liu Y.
        • Ning L.
        • Chen L.
        • Li M.
        • Liu Y.
        • Wang G.
        • et al.
        Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19).
        Front Immunol. 2020; 11: 827
        • Doeppner T.R.
        • Herz J.
        • Gorgens A.
        • Schlechter J.
        • Ludwig A.K.
        • Radtke S.
        • de Miroschedji K.
        • Horn P.A.
        • Giebel B.
        • Hermann D.M.
        Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression.
        Stem Cells Transl Med. 2015; 4: 1131-1143
        • Gimona M.
        • Pachler K.
        • Laner-Plamberger S.
        • Schallmoser K.
        • Rohde E.
        Manufacturing of human extracellular vesicle-based therapeutics for clinical use.
        Int J Mol Sci. 2017; 18
        • Hao Q.
        • Gudapati V.
        • Monsel A.
        • Park J.H.
        • Hu S.
        • Kato H.
        • Lee J.H.
        • Zhou L.
        • He H.
        • Lee J.W.
        Mesenchymal stem cell-derived extracellular vesicles decrease lung injury in mice.
        J Immunol. 2019; 203: 1961-1972
        • Huang R.
        • Qin C.
        • Wang J.
        • Hu Y.
        • Zheng G.
        • Qiu G.
        • Ge M.
        • Tao H.
        • Shu Q.
        • Xu J.
        Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury.
        Aging (Albany NY). 2019; 11: 7996-8014
        • Khatri M.
        • Richardson L.A.
        • Meulia T.
        Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.
        Stem Cell Res Ther. 2018; 9: 17
        • Khoury M.
        • Cuenca J.
        • Cruz F.F.
        • Figueroa F.E.
        • Rocco P.R.M.
        • Weiss D.J.
        Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19.
        Eur Respir J. 2020; 2000858
        • Khoury M.
        • Rocco P.R.M.
        • Phinney D.G.
        • Krampera M.
        • Martin I.
        • Viswanathan S.
        • Nolta J.A.
        • LeBlanc K.
        • Galipeau J.
        • Weiss D.J.
        Cell-based therapies for COVID-19: proper clinical investigations are essential.
        Cytotherapy. 2020;
        • Kordelas L.
        • Rebmann V.
        • Ludwig A.K.
        • Radtke S.
        • Ruesing J.
        • Doeppner T.R.
        • Epple M.
        • Horn P.A.
        • Beelen D.W.
        • Giebel B.
        MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease.
        Leukemia. 2014; 28: 970-973
        • Laffey J.G.
        • Matthay M.A.
        Fifty Years of Research in ARDS. Cell-based therapy for acute respiratory distress syndrome. Biology and potential therapeutic value.
        Am J Respir Crit Care Med. 2017; 196: 266-273
        • Lener T.
        • Gimona M.
        • Aigner L.
        • Borger V.
        • Buzas E.
        • Camussi G.
        • Chaput N.
        • Chatterjee D.
        • Court F.A.
        • Del Portillo H.A.
        • et al.
        Applying extracellular vesicles based therapeutics in clinical trials—an ISEV position paper.
        J Extracell Vesicles. 2015; 4: 30087
        • Liu J.
        • Chen T.
        • Lei P.
        • Tang X.
        • Huang P.
        Exosomes released by bone marrow mesenchymal stem cells attenuate lung injury induced by intestinal ischemia reperfusion via the TLR4/NF-kappaB pathway.
        Int J Med Sci. 2019; 16: 1238-1244
        • Magro C.
        • Mulvey J.J.
        • Berlin D.
        • Nuovo G.
        • Salvatore S.
        • Harp J.
        • Baxter-Stoltzfus A.
        • Laurence J.
        Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
        Transl Res. 2020;
        • Mahida R.Y.
        • Matsumoto S.
        • Matthay M.A.
        Extracellular vesicles: a new frontier for research in acute respiratory distress syndrome.
        Am J Respir Cell Mol Biol. 2020;
        • Mansouri N.
        • Willis G.R.
        • Fernandez-Gonzalez A.
        • Reis M.
        • Nassiri S.
        • Mitsialis S.A.
        • Kourembanas S.
        Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes.
        JCI Insight. 2019; 4
        • Matthay M.A.
        • Calfee C.S.
        • Zhuo H.
        • Thompson B.T.
        • Wilson J.G.
        • Levitt J.E.
        • Rogers A.J.
        • Gotts J.E.
        • Wiener-Kronish J.P.
        • Bajwa E.K.
        • et al.
        Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.
        Lancet Respir Med. 2019; 7: 154-162
        • Mehta P.
        • McAuley D.F.
        • Brown M.
        • Sanchez E.
        • Tattersall R.S.
        • Manson J.J.
        • Hlh Across Speciality Collaboration, U.K
        COVID-19: consider cytokine storm syndromes and immunosuppression.
        Lancet. 2020; 395: 1033-1034
        • Monsel A.
        • Zhu Y.G.
        • Gennai S.
        • Hao Q.
        • Hu S.
        • Rouby J.J.
        • Rosenzwajg M.
        • Matthay M.A.
        • Lee J.W.
        Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice.
        Am J Respir Crit Care Med. 2015; 192: 324-336
        • Morrison T.J.
        • Jackson M.V.
        • Cunningham E.K.
        • Kissenpfennig A.
        • McAuley D.F.
        • O'Kane C.M.
        • Krasnodembskaya A.D.
        Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer.
        Am J Respir Crit Care Med. 2017; 196: 1275-1286
        • Nassar W.
        • El-Ansary M.
        • Sabry D.
        • Mostafa M.A.
        • Fayad T.
        • Kotb E.
        • Temraz M.
        • Saad A.N.
        • Essa W.
        • Adel H.
        Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases.
        Biomater Res. 2016; 20: 21
        • Pachler K.
        • Lener T.
        • Streif D.
        • Dunai Z.A.
        • Desgeorges A.
        • Feichtner M.
        • Oller M.
        • Schallmoser K.
        • Rohde E.
        • Gimona M.
        A Good Manufacturing Practice-grade standard protocol for exclusively human mesenchymal stromal cell-derived extracellular vesicles.
        Cytotherapy. 2017; 19: 458-472
        • Park K.S.
        • Svennerholm K.
        • Shelke G.V.
        • Bandeira E.
        • Lasser C.
        • Jang S.C.
        • Chandode R.
        • Gribonika I.
        • Lotvall J.
        Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10.
        Stem Cell Res Ther. 2019; 10: 231
        • Phinney D.G.
        Functional heterogeneity of mesenchymal stem cells: implications for cell therapy.
        J Cell Biochem. 2012; 113: 2806-2812
        • Phinney D.G.
        • Kopen G.
        • Righter W.
        • Webster S.
        • Tremain N.
        • Prockop D.J.
        Donor variation in the growth properties and osteogenic potential of human marrow stromal cells.
        J Cell Biochem. 1999; 75: 424-436
        • Qin C.
        • Zhou L.
        • Hu Z.
        • Zhang S.
        • Yang S.
        • Tao Y.
        • Xie C.
        • Ma K.
        • Shang K.
        • Wang W.
        • et al.
        Dysregulation of immune response in patients with COVID-19 in Wuhan, China.
        Clin Infect Dis. 2020;
        • Radtke S.
        • Gorgens A.
        • Liu B.
        • Horn P.A.
        • Giebel B.
        Human mesenchymal and murine stromal cells support human lympho-myeloid progenitor expansion but not maintenance of multipotent haematopoietic stem and progenitor cells.
        Cell Cycle. 2016; 15: 540-545
        • Reiner A.T.
        • Witwer K.W.
        • van Balkom B.W.M.
        • de Beer J.
        • Brodie C.
        • Corteling R.L.
        • Gabrielsson S.
        • Gimona M.
        • Ibrahim A.G.
        • de Kleijn D.
        • et al.
        Concise review: developing best-practice models for the therapeutic use of extracellular vesicles.
        Stem Cells Transl Med. 2017; 6: 1730-1739
        • Rohde E.
        • Pachler K.
        • Gimona M.
        Manufacturing and characterization of extracellular vesicles from umbilical cord-derived mesenchymal stromal cells for clinical testing.
        Cytotherapy. 2019; 21: 581-592
        • Silachev D.N.
        • Goryunov K.V.
        • Shpilyuk M.A.
        • Beznoschenko O.S.
        • Morozova N.Y.
        • Kraevaya E.E.
        • Popkov V.A.
        • Pevzner I.B.
        • Zorova L.D.
        • Evtushenko E.A.
        • et al.
        Effect of MSCs and MSC-derived extracellular vesicles on human blood coagulation.
        Cells. 2019; 8
        • Varkouhi A.K.
        • Jerkic M.
        • Ormesher L.
        • Gagnon S.
        • Goyal S.
        • Rabani R.
        • Masterson C.
        • Spring C.
        • Chen P.Z.
        • Gu F.X.
        • et al.
        Extracellular vesicles from interferon-gamma-primed human umbilical cord mesenchymal stromal cells reduce Escherichia coli-induced acute lung injury in rats.
        Anesthesiology. 2019; 130: 778-790
        • Vogel W.
        • Grunebach F.
        • Messam C.A.
        • Kanz L.
        • Brugger W.
        • Buhring H.J.
        Heterogeneity among human bone marrow-derived mesenchymal stem cells and neural progenitor cells.
        Haematologica. 2003; 88: 126-133
        • Wang C.
        • Börger V.
        • Sardari M.
        • Murke F.
        • Skuljec J.
        • Pul R.
        • Hagemann N.
        • Dzyubenko E.
        • Dittrich R.
        • Gregorius J.
        • et al.
        Mesenchymal stromal cell-derived small extracellular vesicles induce ischemic neuroprotection by modulating leukocytes and specifically neutrophils.
        Stroke. 2020; (STROKEAHA119028012)
        • Willis G.R.
        • Fernandez-Gonzalez A.
        • Anastas J.
        • Vitali S.H.
        • Liu X.
        • Ericsson M.
        • Kwong A.
        • Mitsialis S.A.
        • Kourembanas S.
        Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation.
        Am J Respir Crit Care Med. 2018; 197: 104-116
        • Witwer K.W.
        • Van Balkom B.W.M.
        • Bruno S.
        • Choo A.
        • Dominici M.
        • Gimona M.
        • Hill A.F.
        • De Kleijn D.
        • Koh M.
        • Lai R.C.
        • et al.
        Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications.
        J Extracell Vesicles. 2019; 81609206
        • Worthington E.N.
        • Hagood J.S.
        Therapeutic use of extracellular vesicles for acute and chronic lung disease.
        Int J Mol Sci. 2020; 21: 2318
        • Yang Y.
        • Shen C.
        • Li J.
        • Yuan J.
        • Yang M.
        • Wang F.
        • Li G.
        • Li Y.
        • Xing L.
        • Peng L.
        • et al.
        Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome.
        medRxiv. 2020; (2020.2003.2002.20029975)
        • Zhu Y.G.
        • Feng X.M.
        • Abbott J.
        • Fang X.H.
        • Hao Q.
        • Monsel A.
        • Qu J.M.
        • Matthay M.A.
        • Lee J.W.
        Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice.
        Stem Cells. 2014; 32: 116-125
        • Giebel B.
        • Hermann D.M.
        Identification of the right cell sources for the production of therapeutically active extracellular vesicles in ischemic stroke.
        Ann Transl Med. 2019; 7: 188
        • Zhang B.
        • Yeo R.W.Y.
        • Lai R.C.
        • Sim E.W.K.
        • Chin K.C.
        • Lim S.K.
        Mesenchymal stromal cell exosome–enhanced regulatory T-cell production through an antigen-presenting cell–mediated pathway.
        Cytotherapy. 2018; 20: 687-696
        • Zhang B.
        • Yin Y.
        • Lai R.C.
        • Tan S.S.
        • Choo A.B.H.
        • Lim S.K.
        Mesenchymal Stem Cells Secrete Immunologically Active Exosomes.
        Stem cells and development. 2014; 23: 1233-1244