French national research agency
Several teams of I-Stem joined industrial partners – research contract RIB - and French academic teams to address call for proposals from the National Research Agency. A good number of these requests were successful, making ANR an essential institutional financer, in particular for consumables and temporary recruitment.
Program CsCelo (RIB) Embryonic stem cells for sphincter muscle deterioration and cardiomypathies
Coordinator : Celogos (Christian Pinset)
Partners : Genethon (Otto Merten), I-Stem (Marc Peschanski, Michel Pucéat)
The degenerative affections of the muscle, skeletal or cardiac, reach a considerable proportion of the population, which still tends to increase with the ageing of our society. They represent a major problem of public health, against which there is no curative treatment. The intramuscular implant of homologous cells is the only currently considered way to authentically restore muscle. Apart from diffuse myopathies, where the technique runs up against the obstacle of the dispersion of muscle defects, cell therapy is already in phase of clinical trial for the regenerative treatment of affected isolated muscles as heart and urinary sphincter. However, these therapeutic approaches are based on the establishment of stem cells resulting from skeletal muscles, which limits considerably the extension of their indications because each patient thus requires a completely personalized cellular preparation. There does not exist either a source of homologous cells in all cases, and none for cardiac lesions altogether as there is no known stock of cardiomyocytes usable for therapeutic. Human embryonic stem cells (ES), because they can be amplified at will and differentiated into any cell phenotype, in particular myoblasts and cardiomyocytes, represent today a very promising theoretical solution with these problems. We gathered to develop the use of the progeny differentiated from the human ES cells in two principal applications, urinary incontinence by sphincter deterioration on the one hand, cardiac insufficiency by cardiomyopathy on the other hand.
Coordinator : Christophe Gaillard/Muriel Audit (Genosafe)
Partners : Stéphane Viville (Strasbourg), Marc Peschanski (I-Stem)
The objective of the hESCREEN project is to provide to pharmaceutical industry new tools in order to accelerate and to improve the process of discovery of therapeutic products. These new tools will be founded on lines of human stem cells obtained by the derivation of embryos carrying a defective gene at the origin of a monogenic disease. In order to make them usable on an industrial scale, and to ensure a homogeneous production of populations of cells tested, the lines will be genetically modified so that the cells express a gene marker which will do them fluoresce T when they reach a stage and a type of precise differentiation. Design of the gene+vector unit for this genetic engineering, and the application will be the second stage of the hESCREEN project. The development of the products finished for marketing requires the installation and the application of systematic quality controls, genotypic and phonotypical, which seems the third stage of the hESCREEN project. hESCREEN aims at installing a framework allowing the application of the current processes to discover drugs by pharmaceutical industry in monogenic diseases. In a reciprocal way, the hESCREEN will interest the industrialists of the biotechnology of pharmacy while enabling them to better understand, for more frequent diseases, the value of their immense libraries of compounds.
Coordinator : Laurent de Narbonne (LTKfarma)
Partners : José Cohen (CNRS), Philippe Hantraye (CEA), Anselme Perrier (I-Stem)
Coordinator : Daniel Aberdam (INSERM U634)
Partner : Michel Pucéat
Coordinator : Catherine Picart (CNRS Université Montpellier 2 UMR 5539
Partners : Michel Pucéat
Kraine Ginel CNRS UMR 6522- Université de ROUEN The stem cells respond differently to environmental factors including from morphogenesis, the extra cellular matrix or the physical forces which they undergo during embryogenesis (compaction) or transplantation.
We made the assumption that a nano biomimetic material should allow the differentiation of the embryonic stem cells, according to the rigidity of the biofilm.
We develop polypeptide biocompatible multi-layer polymer films and polysaccharides on a nanometric scale. We control 1) the mechanical properties of film 2) the presence of hydrophobic nano-fields for the incorporation of bioactive molecules such as growth promoters 3) the surface properties of film in terms of flexibility of chains and nano-rigidity. The composition and the rigidity of nano films are optimized for the differentiation of the cells ES, more specifically towards the mesoderm.
Coordinator : Michel Pucéat
Partners : Stéphane Blot (School Veterinary, Maison-Alfort)
Alain Berdeaux (INSERM, U660, Créteil)
Virginie Lambert (CNRS UMR 8162 Hospital Marie Lannelongue ) The goal of the project is to test the regenerating potential of embryonic stem cells specified towards the cardiac lineage in two animal models of rare genetic cardiac pathologies: a mini-pig model of the Fallot tetralogy and dogs carrying the Duchenne myopathy: Gold Retriever Muscular Dystrophy.
Fondation leducq réseau transatlantique CAPTAA Cardiac Progenitors TransAtlantic Alliance 2005-2010
Coordinators: K Schwartz (Paris) et KR Chien (Boston)The goal of this network is to understand the biology and to test the potential of cardiac progenitors (isl1+, Oct4+) and of cardiac cells for the cell therapy of genetic or ischemic cardiovascular pathologies
Coordinators : A Hagège (Paris) et R. Levine (Boston)
http://www.mitral.org/ in construction
The goal of this network is to understand better genetic and ischemic pathologies affecting the cardiac valves and to propose new alternative therapies. One of the goals is to propose a cell therapy either by progenitors of the valves or by cardiomyocytes resulting from ES cells in order to modify the ventricle and muscle used as a pillar of the valve. Another goal is to model genetic pathologies affecting the valves with ES cells.
AO ANR 2005
Program CsCelo (RIB) Embryonic stem cells for sphincter muscle deterioration and cardiomypathies
Coordinator : Celogos (Christian Pinset)
Partners : Genethon (Otto Merten), I-Stem (Marc Peschanski, Michel Pucéat)
The degenerative affections of the muscle, skeletal or cardiac, reach a considerable proportion of the population, which still tends to increase with the ageing of our society. They represent a major problem of public health, against which there is no curative treatment. The intramuscular implant of homologous cells is the only currently considered way to authentically restore muscle. Apart from diffuse myopathies, where the technique runs up against the obstacle of the dispersion of muscle defects, cell therapy is already in phase of clinical trial for the regenerative treatment of affected isolated muscles as heart and urinary sphincter. However, these therapeutic approaches are based on the establishment of stem cells resulting from skeletal muscles, which limits considerably the extension of their indications because each patient thus requires a completely personalized cellular preparation. There does not exist either a source of homologous cells in all cases, and none for cardiac lesions altogether as there is no known stock of cardiomyocytes usable for therapeutic. Human embryonic stem cells (ES), because they can be amplified at will and differentiated into any cell phenotype, in particular myoblasts and cardiomyocytes, represent today a very promising theoretical solution with these problems. We gathered to develop the use of the progeny differentiated from the human ES cells in two principal applications, urinary incontinence by sphincter deterioration on the one hand, cardiac insufficiency by cardiomyopathy on the other hand.
AO ANR 2006
Program HESCREEN (RIB) Etablissement d'une banque de lignées de cellules souches issues d'embryons porteurs d'une maladie monogénique, génétiquement modifiées en vue d'usage industriel dans le criblage à haut débit de composés d'intérêt pharmaceutique
Coordinator : Christophe Gaillard/Muriel Audit (Genosafe)
Partners : Stéphane Viville (Strasbourg), Marc Peschanski (I-Stem)
The objective of the hESCREEN project is to provide to pharmaceutical industry new tools in order to accelerate and to improve the process of discovery of therapeutic products. These new tools will be founded on lines of human stem cells obtained by the derivation of embryos carrying a defective gene at the origin of a monogenic disease. In order to make them usable on an industrial scale, and to ensure a homogeneous production of populations of cells tested, the lines will be genetically modified so that the cells express a gene marker which will do them fluoresce T when they reach a stage and a type of precise differentiation. Design of the gene+vector unit for this genetic engineering, and the application will be the second stage of the hESCREEN project. The development of the products finished for marketing requires the installation and the application of systematic quality controls, genotypic and phonotypical, which seems the third stage of the hESCREEN project. hESCREEN aims at installing a framework allowing the application of the current processes to discover drugs by pharmaceutical industry in monogenic diseases. In a reciprocal way, the hESCREEN will interest the industrialists of the biotechnology of pharmacy while enabling them to better understand, for more frequent diseases, the value of their immense libraries of compounds.
AO ANR 2007
Program TK-safe (RIB) The "safety switch": ensuring post-grafting safety riddance of cell therapy products with the TK-suicide gene strategy
Coordinator : Laurent de Narbonne (LTKfarma)
Partners : José Cohen (CNRS), Philippe Hantraye (CEA), Anselme Perrier (I-Stem)
The cellular therapy is currently a therapeutic approach in the course of evaluation in a number of pathologies unceasingly growing (neurodegenerative diseases, muscular infarctions, cancer,…) This approach rests on the replacement of non functional cells by relevant exogenous cells. However, whatever the cell type considered, a constant risk exists that the cells injected exert a deleterious effect on the grafted patient. There is no procedure to date allowing elimination of these cells in vivo, in the event of a major side effect. This is the principal safety obstacle with the development of cell therapy and, conversely, potentially represents the possibility of an access to a considerable market. This is the principal objective of this research program. The system suggested rests on a genetic engineering of cells before their injection allowing the expression of a gene in each therapeutic cell that would allow them to “commit suicide” and the possibility of eliminating them “at will” in vivo. LTKfarma, the leader of the project, has exclusive rights of exploitation for the TK suicide gene system, in partnership with the University Paris 6 via 31 patents in Europe, the United States and Japan. Its ambition is to become a world leader in the security of cell therapy.
ANR White program 2006 HUES cell signature
Coordinator : Daniel Aberdam (INSERM U634)
Partner : Michel Pucéat
The lines of human embryonic stem cells (huES), derived from the mass intern of the blastocyst, have the capacity to proliferate indefinitely while keeping the potential to differentiate into any cell type resulting from the three embryonic layers. These cells represent a formidable tool to replicate in vitro the various stages of the normal and pathological embryonic development and is used as single cell model to identify on a molecular scale genes and signalling pathways implied in embryonic physiopathology. The destiny of these cells in a particular engagement must be permanently under the space and temporal strict control of a genetic and epigenetic flexible program. To obtain a total view of the networks of regulation in these cells during their differentiation, a combination of experimental approaches is essential. The objective of our project is to characterize two major networks of gene regulation: (I) the evolutionary cell transcriptase of huES in the course of their engagement towards ectoderm and mesoderm on the one hand, and of their differentiation in cardiomyocytes, epidermic and corneal cells, (II) miRNAs implied in these processes and the study of their role and of their target genes in vitro (huES) and in vivo (murine blastocysts and embryos).
A functional genomic study of identified target genes will be undertaken by siRNA and exogenic overexpression during the in vivo development and the induced differentiation of the huES. This project combines global experimental solutions (ChIP-on-chip) and innovative techniques such as the expression of miRNA in vivo and in vitro (2 ' - O-Methyloligonucleotide).
A functional genomic study of identified target genes will be undertaken by siRNA and exogenic overexpression during the in vivo development and the induced differentiation of the huES. This project combines global experimental solutions (ChIP-on-chip) and innovative techniques such as the expression of miRNA in vivo and in vitro (2 ' - O-Methyloligonucleotide).
ANR pNano BIOACTIFILMS 2006
Coordinator : Catherine Picart (CNRS Université Montpellier 2 UMR 5539
Partners : Michel Pucéat
Kraine Ginel CNRS UMR 6522- Université de ROUEN
We made the assumption that a nano biomimetic material should allow the differentiation of the embryonic stem cells, according to the rigidity of the biofilm.
We develop polypeptide biocompatible multi-layer polymer films and polysaccharides on a nanometric scale. We control 1) the mechanical properties of film 2) the presence of hydrophobic nano-fields for the incorporation of bioactive molecules such as growth promoters 3) the surface properties of film in terms of flexibility of chains and nano-rigidity. The composition and the rigidity of nano films are optimized for the differentiation of the cells ES, more specifically towards the mesoderm.
ANR Rares diseases 2006 CARDIOSTEM
Potentiel of embryonic stem cells in the treatment of cardiomyopathies
Coordinator : Michel Pucéat
Partners : Stéphane Blot (School Veterinary, Maison-Alfort)
Alain Berdeaux (INSERM, U660, Créteil)
Virginie Lambert (CNRS UMR 8162 Hospital Marie Lannelongue )
Fondation leducq réseau transatlantique CAPTAA Cardiac Progenitors TransAtlantic Alliance 2005-2010
Coordinators: K Schwartz (Paris) et KR Chien (Boston)
Fondation leducq réseau transatlantique MITRAL 2007-2012
Coordinators : A Hagège (Paris) et R. Levine (Boston)
http://www.mitral.org/ in construction
The goal of this network is to understand better genetic and ischemic pathologies affecting the cardiac valves and to propose new alternative therapies. One of the goals is to propose a cell therapy either by progenitors of the valves or by cardiomyocytes resulting from ES cells in order to modify the ventricle and muscle used as a pillar of the valve. Another goal is to model genetic pathologies affecting the valves with ES cells.
