Extracellular Vesicles – From Bench to Bedside (SEVRIT)

 Verena Börger, Peter A. Horn, Bernd Giebel
Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen

Human mesenchymal stem/stromal cells (MSCs) represent a promising tool in regenerative medicine. Up to now, more than 700 NIH-registered clinical trials investigated their therapeutic potential in various diseases. Despite controversial reports regarding the efficacy of MSC-treatments, in many applications MSCs seem to exert their beneficial effects rather in a paracrine manner than by cell replacement. In this context, extracellular vesicles (EVs), such as exosomes (70-150 nm) and microvesicles (100-1,000 nm), are discussed to execute the MSCs’ therapeutic effects (Börger et al., 2016; Börger et al., 2015; Lener et al., 2015). Our previous studies revealed promising therapeutic activities of MSC-EVs in an acute steroid refractory Graft-versus-Host Disease (aGvHD) patient (Kordelas et al., 2014), in a murine ischemic stroke model (Doeppner et al., 2015), in a sheep model for hypoxia induced fetal brain damage (Ophelders et al., 2016), and a neonatal rat model for inflammation induced brain damage in preterms (Drommelschmidt et al., 2016).

Aiming to qualify MSC-EVs as a novel therapeutic agent to treat different patient cohorts (initially additional aGvHD patients), we have optimized the large scale production of MSC-EVs in a clinical grade compatible manner. For the translation into the clinics MSC-EV production processes have to be standardized in a GMP compatible manner, now, and get qualified and validated. Furthermore, quality release criteria have to be defined (Lener et al., 2015).

Within our project, which is part of a consortium funded by the EFRE.NRW program of the European Union and the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen (SEVRIT - Produktion und Qualitätssicherung von Stammzell-abgeleiteten extrazellulären Vesikeln für neuartige regenerative und immunmodulierende Therapieansätze), we address the required issues to be fulfilled to successfully apply for a production licence of MSC-EVs at the local regulatory authorities. A production licence is mandatory to apply for clinical studies.

Börger, V., Bremer, M., Görgens, A., and Giebel, B. (2016). Mesenchymal stem/stromal cell-derived extracellular vesicles as a new approach in stem cell therapy. ISBT Science Series 11, 228-234.

Börger, V., Görgens, A., Rohde, E., and Giebel, B. (2015). Therapeutisches Potenzial von extrazellulären Vesikeln aus mesenchymalen Stamm- bzw. Stromazellen. Transfusionsmedizin - Immunhämatologie, Hämotherapie, Immungenetik, Zelltherapie 5, 131-137.

Doeppner, T.R., Herz, J., Görgens, A., Schlechter, J., Ludwig, A.K., Radtke, S., de Miroschedji, K., Horn, P.A., Giebel, B., and Hermann, D.M. (2015). Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression. Stem Cells Transl Med 4, 1131-1143.

Drommelschmidt, K., Serdar, M., Bendix, I., Herz, J., Bertling, F., Prager, S., Keller, M., Ludwig, A.K., Duhan, V., Radtke, S., et al. (2016). Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury. Brain Behav Immun.

Kordelas, L., Rebmann, V., Ludwig, A.K., Radtke, S., Ruesing, J., Doeppner, T.R., Epple, M., Horn, P.A., Beelen, D.W., and Giebel, B. (2014). MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28, 970-973.

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. (2015). Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles 4, 30087.

Ophelders, D.R., Wolfs, T.G., Jellema, R.K., Zwanenburg, A., Andriessen, P., Delhaas, T., Ludwig, A.K., Radtke, S., Peters, V., Janssen, L., et al. (2016). Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia. Stem Cells Transl Med 5, 754-763.