Securitized production of adipose-derived stromal cells for cell therapy – SAFE

In recent years, relevant data have indicated that mesenchymal stroma/stem cells (MSC) can be used as reparative/regenerative cells to treat a broad range of clinical conditions including immunological implications as well as degenerative situations, creating a great hope to treat a wide range of pathologies including degenerative diseases or tissue replacement. More recently, many studies including ours reveal that adipose tissues can represent a large and convenient reservoir of cells close to MSC from bone marrow, which represent the gold standard in this field. These cells were named adipose derived stroma/stem cells or ASC. They display strong similarities with MSC from bone marrow but also some differences. We (STROMALab, team 1) have patented several of these aspects, among them their strong angiogenic property. This is currently investigated at clinical level in Toulouse after EFS-PM have set-up a GMP protocol. Another important application of MSC and ASC is their use to help the regeneration of epithelia. In association with CEA we (STROMALab, team 1) have patented the use of ASC in skin wound healing. Up to now, the cell therapy use mesenchymal stromal/stem cells either for autologous or allogeneic settings. On one hand, autologous administration have the advantage of avoiding immune conflicts and minimizing pathogens transmission; but the age of the donor and its underlying pathology may influence the quality of the cell product. On the other hand, allogeneic cell product could be done with carefully selected young adults that minimize the two above mentioned problems. However, to be operationally and financially efficient, a significant number of allogeneic cell products must be prepared with one harvest. Because of the necessary small size of the donation, this involves inducing a large proliferation of the cells and thus may lead to senescence or to increase the transformation risk. Clinical trials using cultured mesenchymal stromal/stem cells (more than 80 for MSC and more than 10 for ASC, source www.clinicaltrial.gov) are currently ongoing. Despite this, the changes induced by the culture process (i.e. reduction in differentiation potential, alteration of the redox metabolism etc.) are still poorly understood. This may lead to inadequacy between the planned and the real therapeutic effect. Furthermore, in Europe, a new regulation (1394/2007) has came into force since 2008 on advanced therapy medicinal products (ATMP) that includes adult stem cells. European Medicines Agency (EMA) has begun to edict guidelines on their development before marketing authorization. These recommendations underline the importance of the information which must be provided on the modifications led by the process of culture, and risks of which they are linked to. Thus when academics want to transfer their knowledge and know-how to an industrial partner, they must follow those guidelines. The present proposal, in the framework of industrial research, is aimed at expanding pre-clinical knowledge on cultured ASC. Our project will study the genetic stability of cultured stromal cells, the changes induced by the culture process on the risk of senescence and transformation, especially the role of oxidative stress and the influence of the donor characteristics on those parameters. This will lead us to test the safety of ASC, in vivo, in immunocompromise rodent models and finally to design accurate quality controls to enhance the safety of the cell product. In addition, the completed works will be able to lead to the definition of new conditions of culture, reducing its impact on the physiology of the ASC.