MATRIXCELL

Cardiovascular diseases remain the leading cause of death in developed countries. Conventional treatments usually fail and these diseases represent a main target for cell therapy. Clinical trials of first generation have been performed with heterogeneous cell populations. They showed a poor efficiency with transient improvement of functional parameters, probably related to a paracrine effect of the injected cells. The current trend is to use more homogeneous cell populations and also to take into consideration the environment of injected cells. Our project will be developed in this context. We will regenerate the vascular system in ischemic diseases by a cell therapy approach and by repairing the extracellular matrix, highly degraded in these diseases. For this "matricial therapy”, we will use synthetic GlycosAminoGlycans (GAG), mimicking the properties of natural GAGs, key elements of the extracellular matrix. These molecules bind themselves to growth factors and cytokines and increase their efficacy. Industrial Partner 3 has identified two lead GAG mimetics, active on mature endothelial cells (EC). Preliminary results (Partners 1 and 2) showed that these leads can increase the formation of circulating endothelial progenitors (EPC) derived colonies. The extracellular matrix of endothelial cells also stimulates the formation of these colonies. The project takes into account these concepts and preliminary data. It aims to create a new generation of therapy products associating cells and matrix compounds in a serum free medium. Le projet s’articule autour de ces concepts et données préliminaires. Il a pour but de créer une nouvelle génération de produits thérapeutiques associant cellules et composés matriciels dans un milieu sans sérum. The EC will be produced by partner 2, from adult peripheral blood (autologous to the patient) or from cord blood, if the quantity and quality of adult cells are not optimal. The cord blood EPC-derived EC are allogeneic, but they generate more colonies and have a capacity of proliferation significantly higher than their adult equivalent. The matricial products will be composed of first-generation lead GAG mimetics or of second generation GAG mimetics taking in account the structure of natural GAGs (partner 2) isolated from EC or ischemic tissues in regeneration. These last molecules will be selected on their significant activity on the formation of colonies derived from EPC and on the proliferation of EC derived from it. The serum-free medium, produced by industrial partner 4 will be supplemented with GAG mimetics of first and second generation produced by partner 3, and the potentiating effect of GAGs on heparin binding growth factors will be analyzed by partner 2. The effectiveness of this medium containing GAG mimetics will be evaluated by partner 2 on EC derived EPC, and by partner 5 in animal models of cardiac and hind limbs ischemia. In these animal models, partner 5 will analyze the efficacy of cell therapy by measuring cardiac and vascular functions. EC will be produced in GMP conditions, enabling a rapid transition to clinical trials. For this, cells will be grown in a closed system in an optimized culture medium containing the most active GAG mimetic. The objective is to generate a maximal number of colonies, with high proliferation potential. This will enable the production, preferably from adult EPC, of a cell dose compatible with therapeutic use, while limiting the number of passages, which may affect cell integrity by generating genomic instability. The integrity of the genome of these cells will be analyzed. Overall, incorporating endothelial cells derived from EPC, serum-free medium and matrix elements (GAG) will generate new products for in vitro cell culture and in vivo therapies.