Introduction
What is CASCADE?
CASCADE, Cultivated Adult Stem Cells as Alternative for Damaged tissuE, is a consortium granted by the 7th Framework Program of the European Commission. It has the aim to develop processes following Good Manufacturing Practice (GMP) for producing adult stem cells, more precisely for the generation of Mesenchymal Stromal/Stem Cells (MSCs). These GMP produced MSC-derived cellular products are planned to be clinically used for the repair of damaged skin and cornea. As a consortium, CASCADE tightly links together a unique set of public and private institutions as well as small and medium enterprises (SMEs) representing well recognized experts, knowledge and know-how in the field of stem cell research, translational research, and clinical development of cellular products.
Starting with known procedures, CASCADE will develop innovative technologies based on the expertise of its partners. Among our research themes, the specific issue of multiple recipients and universal donors will be investigated. To this end, human MSC will be derived by GMP conform methods from different tissues such as bone marrow, adipose tissue, cord blood, and amniotic membrane. The biologic functional features of GMP produced MSC will be evaluated by in vitro and in vivo models, and the immunological consequences of MSC transplantation will be studied. Additionally, the issue of product safety will be a major topic of this research program, and CASCADE will work on establishing standards to completely control the crucial steps of cell production, and therefore to ensure that the clinical use of MSCs will be as safe as possible. Moreover, during the whole CASCADE initiative, ethical and legal issues raised as a result of MSC therapies will be considered. Direct collaboration within two networks of clinical experts will allow CASCADE to finely tune production specifications, and to define optimal clinical protocols for MSC-based cellular therapies.
The outcome is a consortium that encompasses all the technologies and skills required to efficiently develop innovative technologies for the production of clinical grade MSC, and to translate this production into a cellular drug supporting wound healing.
What are MSCs?
First described in bone marrow by Friedenstein in seventies, MSCs are present in all tissues. MSCs demonstrate not only a wide range of differentiation potential, ranging from bone to nervous tissue, but exhibit immunosuppressive and anti-inflammatory effects that will be essential on the repair and healing of damaged tissue. Moreover, they produce numerous cytokines, chemokines and growth factors that allow them to rescue suffering cells, to attract local stem cells and to help the rebuilt of the normal tissue structure. Based on all these large range of actions, MSCs have a central action for rebuilding tissues as bone and cartilage, and for repairing damaged tissue (e.g. cornea and skin) after wounds. During the wounds repair, MSCs act by different ways one of them is to finely tune the inflammation and local/general immune reaction. All of the actions of MSCs lead to a switch from scar to repair.
Since the end of last century, MSCs have been produced and used in various clinical settings ranging from bone repair to immunological intervention. However, despite the great interest in use of MSCs for immune intervention and regenerative medicine, definitive standards for their production are still lacking. Moreover, simple standard controls for their production have been described, but because of the complexity of cell therapy (far beyond that for classical drug therapy), specific controls must be developed. Implementing more sensitive analyses at the genomic level and performing a long-term survey of patients receiving MSCs will be important. So far, numerous clinical trials but few well-conducted demonstrative clinical trials have been performed. Building robust phase II/phase III trials for all potential indications is urgently needed. These trials should be in accordance with the guidelines recently proposed by the International Society for Stem Cell Research (www.isscr.org/clinical_trans). Considering all the fields involved, the production and clinical use of MSC must take place in interactive networks with close involvement of fundamental research teams, research and development sectors, production laboratories and clinical teams. Because lessons from clinical trials must be taken into account, only such integrative research consortiums will allow for the transfer of MSCs from the bench to the bedside and back.
