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      Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper

      research-article
      1 , 2 , 1 , 2 , 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 3 , 21 , 22 , 23 , 24 , 25 , 26 , 3 , 27 , 28 , 29 , 30 , 1 , 2 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 32 , 8 , 9 , 45 ,   46 , 47 , 1 , 2 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 52 , 55 , 7 , 56 , 1 , 2 , * , 3 , *
      Journal of Extracellular Vesicles
      Co-Action Publishing
      immunology, neurobiology, haematology, stem cells, tissue regeneration, tumour vaccination, regulation

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          Abstract

          Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

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          Most cited references194

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          Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.

          Adult bone-marrow-derived mesenchymal stem cells are immunosuppressive and prolong the rejection of mismatched skin grafts in animals. We transplanted haploidentical mesenchymal stem cells in a patient with severe treatment-resistant grade IV acute graft-versus-host disease of the gut and liver. Clinical response was striking. The patient is now well after 1 year. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.
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            Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes

            Using ferritin-labeled protein A and colloidal gold-labeled anti-rabbit IgG, the fate of the sheep transferrin receptor has been followed microscopically during reticulocyte maturation in vitro. After a few minutes of incubation at 37 degrees C, the receptor is found on the cell surface or in simple vesicles of 100-200 nm, in which the receptor appears to line the limiting membrane of the vesicles. With time (60 min or longer), large multivesicular elements (MVEs) appear whose diameter may reach 1-1.5 micron. Inside these large MVEs are round bodies of approximately 50-nm diam that bear the receptor at their external surfaces. The limiting membrane of the large MVEs is relatively free from receptor. When the large MVEs fuse with the plasma membrane, their contents, the 50-nm bodies, are released into the medium. The 50-nm bodies appear to arise by budding from the limiting membrane of the intracellular vesicles. Removal of surface receptor with pronase does not prevent exocytosis of internalized receptor. It is proposed that the exocytosis of the approximately 50-nm bodies represents the mechanism by which the transferrin receptor is shed during reticulocyte maturation.
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              Cooling for newborns with hypoxic ischaemic encephalopathy.

              Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects. To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects. We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.
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                Author and article information

                Journal
                J Extracell Vesicles
                J Extracell Vesicles
                JEV
                Journal of Extracellular Vesicles
                Co-Action Publishing
                2001-3078
                31 December 2015
                2015
                : 4
                : 10.3402/jev.v4.30087
                Affiliations
                [1 ]Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria
                [2 ]Department of Blood Group Serology and Transfusion Medicine, University Hospital, Salzburger Landeskliniken GesmbH (SALK), Salzburg, Austria
                [3 ]Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
                [4 ]Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
                [5 ]Molecular Biotechnology Center, Department of Medical Sciences, University of Turin, Turin, Italy
                [6 ]Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US23 Inserm, Villejuif, France
                [7 ]Centre of Clinical Investigation in Biotherapy CICBT 1248, Institut Gustave Roussy, Villejuif, France
                [8 ]Division of Hematology & Oncology, Rhode Island Hospital, Providence, RI, USA
                [9 ]The Alpert Medical School of Brown University, Providence, RI, USA
                [10 ]Department of Physiology, Faculty of Biology, Pontificia-Universidad Católica de Chile, Santiago, Chile
                [11 ]ICREA at Barcelona Centre for International Health Research (CRESIB), Hospital Clínic – Universitat de Barcelona, Barcelona, Spain
                [12 ]Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
                [13 ]School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland;
                [14 ]Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
                [15 ]Anti-Tumor Drugs Section, Department of Therapeutic Research and Medicines Evaluation, National Institute of Health (ISS), Rome, Italy
                [16 ]Metabolomics Unit, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, Derio, Spain
                [17 ]IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
                [18 ]Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
                [19 ]Departament de Producció Animal, ETSEA, Universitat de Lleida, Lleida, Spain
                [20 ]Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
                [21 ]Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA
                [22 ]James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
                [23 ]Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium
                [24 ]Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
                [25 ]Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia
                [26 ]Massachusetts General Hospital, Boston, MA, USA
                [27 ]Department of Surgery, YLL School of Medicine, NUS, Singapore, Singapore
                [28 ]Department of Bone Marrow Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
                [29 ]Experimental Perinatology/Neonatology, School of Mental Health and Neuroscience, School of Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
                [30 ]Molecular Cell Biology and Focus Program Translational Neurosciences, University of Mainz, Mainz, Germany
                [31 ]Research and Cell Services, Finnish Red Cross Blood Service, Helsinki, Finland
                [32 ]Division of Stem Cell Neurobiology, Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
                [33 ]European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK
                [34 ]Department of Cell Biology, Center for Molecular Medicine, University Medical Center, Utrecht, The Netherlands
                [35 ]Institute of Medical Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
                [36 ]Krefting Research Centre, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [37 ]Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
                [38 ]Dpto. Biología Celular y Parasitologia, Facultat de Farmacia, Universitat de Valencia, Valencia, Spain
                [39 ]Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Universitat de València-Health Research Institute La Fe, Valencia, Spain
                [40 ]Institute for Environmental Health Sciences and Hospital Infection Control Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
                [41 ]Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
                [42 ]Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
                [43 ]Centre for Cardiovascular Research, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
                [44 ]Mass Spectrometry and Proteomics, Institute of Biosciences and BioResources, National Research Council of Italy, Naples, Italy
                [45 ]BASG – Bundesamt für Sicherheit im Gesundheitswesen – Federal Office for Safety in Health Care, AGES – Agentur für Gesundheit und Ernährungssicherheit – Austrian Agency for Health and Food Safety, Institut Überwachung – Institute Surveillance, Wien, Austria
                [46 ]Institute of Molecular Regenerative Medicine, Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria;
                [47 ]Ralf Sanzenbacher, Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel, Federal Institute for Vaccines and Biomedicines, Langen, Germany
                [48 ]Cell Therapy Facility, Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
                [49 ]Experimental & Clinical Cell Therapy Institute, Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
                [50 ]Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Dresden, Germany
                [51 ]Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands
                [52 ]Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
                [53 ]Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
                [54 ]Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
                [55 ]Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
                [56 ]INSERM U932, Institut Curie, Paris, France
                Author notes
                [* ]Correspondence to: Eva Rohde, Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), AT-5020 Salzburg, Austria; Department of Blood Group Serology and Transfusion Medicine, University Hospital, Salzburger Landeskliniken GesmbH (SALK), Lindhofstraße 20-22, AT-5020 Salzburg, Austria, Email e.rohde@ 123456salk.at ; Bernd Giebel, Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany, Email: bernd.giebel@ 123456uk-essen.de
                Article
                30087
                10.3402/jev.v4.30087
                4698466
                26725829
                e5db70ce-f88d-4ffc-98b8-8b25f2d34a28
                © 2015 Thomas Lener et al.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 October 2015
                : 11 December 2015
                : 13 December 2015
                Categories
                Position Paper

                immunology,neurobiology,haematology,stem cells,tissue regeneration,tumour vaccination,regulation

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