66
EUROPEAN COMMISSION PROJECT SUMMARIES
In order to validate the skin equivalent production process, we had to demonstrate our capability to produce, transport, and graft large skin equivalents in a condition similar to that which will be used on the patients (test of the surgical procedure, different dressings, the biological glue versus staples/ stiches, and level of excision). For that purpose, we have produced a large skin equivalent made of normal human keratinocytes and fibroblasts. Four 25 cm2 wound beds have been prepared and grafted with human skin equivalents onto the facia of an 8-week-old pig and followed up for 30 days. The results demonstrated the formation of a well-differentiated, pluristratified epidermis adherent to the underlying dermis, with no difference between the grafts stitched with staples or glued with the fibrin glue. Expected Outcome
It is expected that by translating the results of basic research into curative clinical applications, GENEGRAFT will positively affect the welfare of the patients and public health system. Achieving this project will constitute a proof of principle of the safety and efficacy of ex vivo gene therapy for these severe forms of epidermolysis bullosa using transplantation of genetically corrected skin equivalents. If successful, it will lead to proposing a phase II clinical trial to a larger number of patients. The expected clinical benefits should prevent the occurrence of the most severe complications of the disease, thus improving the functional and vital prognosis of RDEB sufferers, and it is expected that this model could be extended to other genetic skin diseases. Major Publications
ClinicalTrials.gov. Study of Immune Tolerance and Capacity for Wound Healing of Patients With Recessive Dystrophic
Epidermolysis Bullosa (RDEB). ClinicalTrials.gov Identifier: NCT01874769.
Coordinator: Alain Hovnanian, [email protected] Partners: The GENEGRAFT consortium brought together 8 partners from 4 European countries. Alain Hovnanian, Institut National de la Sante´ et de la Recherche Me´dicale, France. Christine Bodemer, Necker Hospital for Sick Children, Assistance Publique Hoˆpitaux de Paris, France. John McGrath, King’s College London, United Kingdom. Klaus Ku¨hlcke, Europa¨isches Institut zur Forschung und Entwicklung von Transplantationsstrategien GmbH, Germany. Didier Caizergues, Association Genethon, France. Patricia Joseph-Mathieu, Inserm Transfert S.A., France. Clare Robinson, DEBRA International Globales Epidermolysis Bullosa Selbsthilfe-Netzwerk Verein, United Kingdom. Michele De Luca, Universita degli Studi di Modena e Reggio Emilia, Italy. Website: www.genegraft.eu Disclaimer
The views expressed in this publication are the sole responsibility of the authors and do not necessarily reflect the official position of the European Commission. Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use that might be made of the information contained in this article.
DOI: 10.1089/humc.2014.2509
Therapeutic Challenge in Leukodystrophies: Translational and Ethical Research Toward Clinical Trials (LeukoTreat) Contract No.: 241622; EC contribution: e 5,978,126; Total costs: e 9,249,281.30; Starting date: 01/03/2010; Duration: 42 months
Background and Objectives
L
eukodystrophies (LDs) are rare inherited neurodegenerative diseases that affect the white matter (myelin) within the central nervous system and sometimes also within the peripheral nerves. These diseases affect mostly children and result from mutations of more than 25 different genes that impair the normal functions of oligodendrocytes or astrocytes. Despite advances made in the past decade in the identification of genetic causes of LDs, there is no current curative therapy. The development of therapeutic approaches for myelin repair and neuroprotection was the main objective of the LeukoTreat project.
The global aim of the project was to promote the development of new therapeutic strategies for the largest number of LDs by combining the expertise of European fundamental and clinical research teams with two small and mediumsized enterprises and experts in medical ethics with LD patients and families associations. The LeukoTreat project developed five complementary success approaches in five WorkPackages (WPs), one of which was fully dedicated to gene and cell therapies for LDs (WP4): 1. WP1—characterizing LDs for therapies aimed at collecting through a unique European database the
EUROPEAN COMMISSION PROJECT SUMMARIES
2.
3.
4.
5.
clinical data, mutations, and biological samples of more than 500 patients to improve knowledge on the epidemiology, the natural history of each LD, and the genotype–phenotype correlation of LDs. WP2—identifying biomarkers aimed at validating, optimizing, and investigating the signification of biomarkers already identified in biological fluids or cells from LD patients, and screening for new biomarkers of oxidative stress, a cellular response common to different forms of LDs, and applying to LDs an innovative lipidomics analysis for the detection of new biomarkers. WP3—developing pharmacological strategies aimed at screening (a) in yeast, molecules that upregulate the eIF2B activity for CACH LD; (b) in oligodendrocytes, molecules that could lower the toxic effect of proteololipid (PLP) gene overexpression for Pelizaeus–Merzbacher (PMD); (c) testing in X-linked adrenoleukodystrophy (X-ALD) and PMD mouse models the use of anti-oxidant, anti-inflammatory, or neuroprotective compounds; and (d) in a mouse model of metachromatic leukodystrophy (MLD), the use of enzyme replacement therapy. WP4—developing innovative gene and cell therapies aimed to (a) pursue and interpret the ongoing clinical trials using hematopoietic stem cell (HSC) gene therapy with lentiviral vector (LV) for X-ALD and MLD, a strategy with potential applications for other selected LDs; (b) unravel the mechanisms of disease correction after allogeneic HSC transplantation or HSC gene therapy with LV by studying in mice brain microglia reconstitution after transplantation; (c) test in mice and/or nonhuman primates the efficacy of direct intracerebral delivery of adeno-associated virus vectors (AAV) for Canavan disease and MLD; (d) test in mouse model of PMD caused by duplication of the PLP gene, a gene silencing approach to inhibit PLP gene expression in oligodendrocytes; (e) evaluate in mouse models the efficacy of neural stem cell (NSC) transplantation to treat PMD and MLD. WP5—tackling ethical impacts of the proposed therapeutic challenges by integrating the participation of patients driven by a well-experienced research team strongly skilled in ethics.
Main Findings and Expected Outcome
In the field of gene and cell therapies, the LeukoTreat research teams have brought new hopes in rare disorders by demonstrating the potential of cell and gene therapy in clinics and at a preclinical stage. Partners of this project participated in this effort as follows:
Developing two phase I/II clinical trials based on the transplantation of autologous HSCs corrected ex vivo with LV for X-ALD and MLD showing efficacy and safety. Proof of concept of this strategy has also been made in a mouse model of globoid cell leukodystrophy (GLD). Developing important preclinical steps in mice and nonhuman primates toward intracerebral AAV gene therapy trials for MLD and Canavan disease Establishing in mice a proof of principle for the use of NSCs overexpressing GALC or ARSA enzymes for MLD and GLD
67
Demonstrating the feasibility and efficacy of a combined strategy based on NSC transplant and HSC gene therapy with LV in a GLD mouse model A phase I/II trial of intracerebral AAV gene therapy for MLD is now open for recruitment. If the proof of concept in mice can be achieved relatively rapidly, the next challenge is to accelerate the translation to clinical trials in LD patients. This requires evaluating efficiency and safety issues (adverse effects caused by overexpression, off-target expression of therapeutic gene) in large animals, in particular in nonhuman primates. In addition, the costs related to the production of good manufacturing practice vectors and the clinical trial management may require partnership with the pharmaceutical industry. Major Publications (acknowledging LeukoTreat in the field of gene and cell therapies)
Gentner, B., Visigalli, I., Hiramatsu, H., et al. (2010). Identification of hematopoietic stem cells-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci. Transl. Med. 2, 58ra84. Lattanzi, A., Neri, M., Maderna, C., et al. (2010). Widespread enzymatic correction of CNS tissues by a single intracerebral injection of therapeutic lentiviral vector in leukodystrophy mouse models. Hum. Mol. Genet. 19, 2208–2227. Visigalli, I., Ungari, S., Martino, S., et al. (2010). The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cells niche. Blood 116, 1857–1866. Biffi, A., Aubourg, P., and Cartier, N. (2011). Gene therapy for leukodystrophies. Hum. Mol. Genet. 20, R42–R53. Buchet, D., Garcia, C., Deboux, C., et al. (2011). Human neural progenitors cells from different foetal forebrain regions remyelinate the adult mouse spinal cord. Brain 134, 1168– 1183. Gritti, A. (2011). Gene therapy for lysosomal storage disorders. Expert Opin. Biol. Ther. 11, 1153–1167. Neri, M., Ricca, A., di Girolamo, I., et al. (2011). Neural stem cell gene therapy ameliorates pathology and function in a mouse model of globoid cell leukodystrophy. Stem Cells 29, 1559–1571. Visigalli, I., and Biffi, A. (2011). Maintenance of a functional hematopoietic stem cells niche through galactocerebrosidase and other enzymes. Curr. Opin. Hematol. 18, 214–219. Arens, A., Appelt, J.U., Bartholomae, C., et al. (2012). Bioinformatic clonality analysis of next-generation sequencingderived viral vector integration sites. Hum. Gene Ther. Methods 23, 111–118. Capotondo, A., Milazzo, R., Politi, L.S., et al. (2012). Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cells transplantation. Proc. Natl. Acad. Sci. USA 109, 15018–15023. Clarke, L.E., Young, K.M., Hamilton, N.B., et al. (2012). Properties and fate of oligodendrocyte progenitor cells in the corpus callosum, motor cortex, and piriform cortex of the mouse. J. Neurosci. 32, 8173–8185. Piguet, F., Sondhi, D., Piraud, M., et al. (2012). Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum. Gene Ther. 23, 903–914. Biffi, A., Montini, E., Lorioli, L., et al. (2013). Extensive genetic engineering of hematopoiesis with therapeutic benefit in
68
EUROPEAN COMMISSION PROJECT SUMMARIES
metachromatic leukodystrophy patients after lentiviral hematopoietic stem cells gene therapy. Science 341, 1233158. Kra¨geloh-Mann, I., Groeschel, S., Kehrer, C., et al. (2013). Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort. Bone Marrow Transplant. 48, 369–375. Matsas, R., and Baron-Van Evercooren, A. (2013). Glial cell transplantation. In Neuroglia, Section 3. Role of Glial Cells in Disease: Recovery of Neural Functions. H. Kettenman and B. Ramson, ed. (Oxford University Press, New York, NY) pp. 728–745. Regis, S., Corsolini, F., Grossi, S., et al. (2013). Restoration of the normal splicing pattern of the PLP1 gene by means of an antisense oligonucleotide directed against an exonic mutation. PloS One 8, e73633. von Jonquieres, G., Mersmann, N., Klugmann, C.B., et al. (2013). Glial promoter selectivity following AAV-delivery to the immature brain. PLoS One 8, e65646.
Coordinator: Catherine Vaurs-Barrie`re, catherine [email protected] Partners: The LeukoTreat consortium brought together 23 partners from 8 countries. Catherine Vaurs-Barrie`re, Universite´ d’Auvergne Clermont-Ferrand 1, France. Enrico Bertini, Ospedale Pediatrico Bambino Gesu, Italy. Mirella Filocamo, Istituto Giannina Gaslini, Italy. Volkmar Gieselmann, Universitaetsklinikum Bonn, Germany. Patrick Aubourg, Institut National de la Sante´ et de la Recherche Me´dicale, France. Yann Dantal, Soluscience SA, France. Graham David Pavitt, University of Manchester, United Kingdom. Aurora Pujol, Fundacio privada institut d’investigacio biomedica de Bellvitge, Spain.
Klaus-Armin Nave, Max Planck gesellschaft zur foerderung der wissenschaften e.v., Germany. Johannes Berger, Medizinische Universitaet Wien, Austria. Thierry Bordet, Trophos SA, France. David Attwell, University College London, United Kingdom. Alessandra Biffi, Fondazione Centro San Raffaele del Monte Tabor/Fondazione Centro San Raffaele, Italy. Ronald Wanders, Academisch Medisch Centrum, The Netherlands. Gre´goire Moutel, Universite´ Paris Descartes, France. Olivier Degrand, France Europe innovation, France. Guy Alba, Association Europe´enne Contre Les Leucodystrophies, France. Ragnhildur Karadottir, The University of Cambridge, United Kingdom. Odile Bloespflug-Tanguy, Universite´ Paris Diderot— Paris 7, France. Graziela Uziel, Fondazione IRCCS Istituto neurologico Carlo Besta, Italy. Matthias Klugmann, University of New South Wales, Australia. Alfried Kohlschu¨tter, Universitaetsklinikum HamburgEppendorf, Germany. Ingeborg Kra¨geloh-Mann, Eberhard Karls Universitaet Tuebingen, Germany. Website: www.leukotreat.eu Disclaimer
The views expressed in this publication are the sole responsibility of the authors and do not necessarily reflect the official position of the European Commission. Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use that might be made of the information contained in this article.
DOI: 10.1089/humc.2014.2510
Optimization of Stem Cell Therapy for Clinical Trials of Degenerative Skin and Muscle Diseases (OptiStem) Contract No.: 223098; EC contribution: e 11,992,312; Total costs: e 16,564,311.99; Starting date: 01/01/2009; Duration: 60 months
Background and Objectives
Approach and Methodology
T
Epithelial and muscle stem cells were studied through ‘‘omics’’ and functional approaches in vitro, and their lineage was traced in vivo. In addition, stem cell transplantation was analyzed for integration in the diseased tissues, aiming at enhancing engraftment (through enhancing angiogenesis, migration, etc.) and at reducing inflammation and sclerosis that rather hamper their engraftment. First-inhuman clinical trials were started and completed within this network and results have been and are being published.
he overall objective of OptiStem was to integrate a large number of research groups operating at basic, translational, and clinical level on epithelia and skeletal muscle and their disease. Tissue-specific adult stem cells were studied in relation to their basic biology and their potential to treat genetic and acquired diseases of these tissues in small and large preclinical models and in patients. Stem cells were genetically corrected by different tools, mainly in preclinical animal models.
EUROPEAN COMMISSION PROJECT SUMMARIES
In order to validate the skin equivalent production process, we had to demonstrate our capability to produce, transport, and graft large skin equivalents in a condition similar to that which will be used on the patients (test of the surgical procedure, different dressings, the biological glue versus staples/ stiches, and level of excision). For that purpose, we have produced a large skin equivalent made of normal human keratinocytes and fibroblasts. Four 25 cm2 wound beds have been prepared and grafted with human skin equivalents onto the facia of an 8-week-old pig and followed up for 30 days. The results demonstrated the formation of a well-differentiated, pluristratified epidermis adherent to the underlying dermis, with no difference between the grafts stitched with staples or glued with the fibrin glue. Expected Outcome
It is expected that by translating the results of basic research into curative clinical applications, GENEGRAFT will positively affect the welfare of the patients and public health system. Achieving this project will constitute a proof of principle of the safety and efficacy of ex vivo gene therapy for these severe forms of epidermolysis bullosa using transplantation of genetically corrected skin equivalents. If successful, it will lead to proposing a phase II clinical trial to a larger number of patients. The expected clinical benefits should prevent the occurrence of the most severe complications of the disease, thus improving the functional and vital prognosis of RDEB sufferers, and it is expected that this model could be extended to other genetic skin diseases. Major Publications
ClinicalTrials.gov. Study of Immune Tolerance and Capacity for Wound Healing of Patients With Recessive Dystrophic
Epidermolysis Bullosa (RDEB). ClinicalTrials.gov Identifier: NCT01874769.
Coordinator: Alain Hovnanian, [email protected] Partners: The GENEGRAFT consortium brought together 8 partners from 4 European countries. Alain Hovnanian, Institut National de la Sante´ et de la Recherche Me´dicale, France. Christine Bodemer, Necker Hospital for Sick Children, Assistance Publique Hoˆpitaux de Paris, France. John McGrath, King’s College London, United Kingdom. Klaus Ku¨hlcke, Europa¨isches Institut zur Forschung und Entwicklung von Transplantationsstrategien GmbH, Germany. Didier Caizergues, Association Genethon, France. Patricia Joseph-Mathieu, Inserm Transfert S.A., France. Clare Robinson, DEBRA International Globales Epidermolysis Bullosa Selbsthilfe-Netzwerk Verein, United Kingdom. Michele De Luca, Universita degli Studi di Modena e Reggio Emilia, Italy. Website: www.genegraft.eu Disclaimer
The views expressed in this publication are the sole responsibility of the authors and do not necessarily reflect the official position of the European Commission. Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use that might be made of the information contained in this article.
DOI: 10.1089/humc.2014.2509
Therapeutic Challenge in Leukodystrophies: Translational and Ethical Research Toward Clinical Trials (LeukoTreat) Contract No.: 241622; EC contribution: e 5,978,126; Total costs: e 9,249,281.30; Starting date: 01/03/2010; Duration: 42 months
Background and Objectives
L
eukodystrophies (LDs) are rare inherited neurodegenerative diseases that affect the white matter (myelin) within the central nervous system and sometimes also within the peripheral nerves. These diseases affect mostly children and result from mutations of more than 25 different genes that impair the normal functions of oligodendrocytes or astrocytes. Despite advances made in the past decade in the identification of genetic causes of LDs, there is no current curative therapy. The development of therapeutic approaches for myelin repair and neuroprotection was the main objective of the LeukoTreat project.
The global aim of the project was to promote the development of new therapeutic strategies for the largest number of LDs by combining the expertise of European fundamental and clinical research teams with two small and mediumsized enterprises and experts in medical ethics with LD patients and families associations. The LeukoTreat project developed five complementary success approaches in five WorkPackages (WPs), one of which was fully dedicated to gene and cell therapies for LDs (WP4): 1. WP1—characterizing LDs for therapies aimed at collecting through a unique European database the
EUROPEAN COMMISSION PROJECT SUMMARIES
2.
3.
4.
5.
clinical data, mutations, and biological samples of more than 500 patients to improve knowledge on the epidemiology, the natural history of each LD, and the genotype–phenotype correlation of LDs. WP2—identifying biomarkers aimed at validating, optimizing, and investigating the signification of biomarkers already identified in biological fluids or cells from LD patients, and screening for new biomarkers of oxidative stress, a cellular response common to different forms of LDs, and applying to LDs an innovative lipidomics analysis for the detection of new biomarkers. WP3—developing pharmacological strategies aimed at screening (a) in yeast, molecules that upregulate the eIF2B activity for CACH LD; (b) in oligodendrocytes, molecules that could lower the toxic effect of proteololipid (PLP) gene overexpression for Pelizaeus–Merzbacher (PMD); (c) testing in X-linked adrenoleukodystrophy (X-ALD) and PMD mouse models the use of anti-oxidant, anti-inflammatory, or neuroprotective compounds; and (d) in a mouse model of metachromatic leukodystrophy (MLD), the use of enzyme replacement therapy. WP4—developing innovative gene and cell therapies aimed to (a) pursue and interpret the ongoing clinical trials using hematopoietic stem cell (HSC) gene therapy with lentiviral vector (LV) for X-ALD and MLD, a strategy with potential applications for other selected LDs; (b) unravel the mechanisms of disease correction after allogeneic HSC transplantation or HSC gene therapy with LV by studying in mice brain microglia reconstitution after transplantation; (c) test in mice and/or nonhuman primates the efficacy of direct intracerebral delivery of adeno-associated virus vectors (AAV) for Canavan disease and MLD; (d) test in mouse model of PMD caused by duplication of the PLP gene, a gene silencing approach to inhibit PLP gene expression in oligodendrocytes; (e) evaluate in mouse models the efficacy of neural stem cell (NSC) transplantation to treat PMD and MLD. WP5—tackling ethical impacts of the proposed therapeutic challenges by integrating the participation of patients driven by a well-experienced research team strongly skilled in ethics.
Main Findings and Expected Outcome
In the field of gene and cell therapies, the LeukoTreat research teams have brought new hopes in rare disorders by demonstrating the potential of cell and gene therapy in clinics and at a preclinical stage. Partners of this project participated in this effort as follows:
Developing two phase I/II clinical trials based on the transplantation of autologous HSCs corrected ex vivo with LV for X-ALD and MLD showing efficacy and safety. Proof of concept of this strategy has also been made in a mouse model of globoid cell leukodystrophy (GLD). Developing important preclinical steps in mice and nonhuman primates toward intracerebral AAV gene therapy trials for MLD and Canavan disease Establishing in mice a proof of principle for the use of NSCs overexpressing GALC or ARSA enzymes for MLD and GLD
67
Demonstrating the feasibility and efficacy of a combined strategy based on NSC transplant and HSC gene therapy with LV in a GLD mouse model A phase I/II trial of intracerebral AAV gene therapy for MLD is now open for recruitment. If the proof of concept in mice can be achieved relatively rapidly, the next challenge is to accelerate the translation to clinical trials in LD patients. This requires evaluating efficiency and safety issues (adverse effects caused by overexpression, off-target expression of therapeutic gene) in large animals, in particular in nonhuman primates. In addition, the costs related to the production of good manufacturing practice vectors and the clinical trial management may require partnership with the pharmaceutical industry. Major Publications (acknowledging LeukoTreat in the field of gene and cell therapies)
Gentner, B., Visigalli, I., Hiramatsu, H., et al. (2010). Identification of hematopoietic stem cells-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci. Transl. Med. 2, 58ra84. Lattanzi, A., Neri, M., Maderna, C., et al. (2010). Widespread enzymatic correction of CNS tissues by a single intracerebral injection of therapeutic lentiviral vector in leukodystrophy mouse models. Hum. Mol. Genet. 19, 2208–2227. Visigalli, I., Ungari, S., Martino, S., et al. (2010). The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cells niche. Blood 116, 1857–1866. Biffi, A., Aubourg, P., and Cartier, N. (2011). Gene therapy for leukodystrophies. Hum. Mol. Genet. 20, R42–R53. Buchet, D., Garcia, C., Deboux, C., et al. (2011). Human neural progenitors cells from different foetal forebrain regions remyelinate the adult mouse spinal cord. Brain 134, 1168– 1183. Gritti, A. (2011). Gene therapy for lysosomal storage disorders. Expert Opin. Biol. Ther. 11, 1153–1167. Neri, M., Ricca, A., di Girolamo, I., et al. (2011). Neural stem cell gene therapy ameliorates pathology and function in a mouse model of globoid cell leukodystrophy. Stem Cells 29, 1559–1571. Visigalli, I., and Biffi, A. (2011). Maintenance of a functional hematopoietic stem cells niche through galactocerebrosidase and other enzymes. Curr. Opin. Hematol. 18, 214–219. Arens, A., Appelt, J.U., Bartholomae, C., et al. (2012). Bioinformatic clonality analysis of next-generation sequencingderived viral vector integration sites. Hum. Gene Ther. Methods 23, 111–118. Capotondo, A., Milazzo, R., Politi, L.S., et al. (2012). Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cells transplantation. Proc. Natl. Acad. Sci. USA 109, 15018–15023. Clarke, L.E., Young, K.M., Hamilton, N.B., et al. (2012). Properties and fate of oligodendrocyte progenitor cells in the corpus callosum, motor cortex, and piriform cortex of the mouse. J. Neurosci. 32, 8173–8185. Piguet, F., Sondhi, D., Piraud, M., et al. (2012). Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum. Gene Ther. 23, 903–914. Biffi, A., Montini, E., Lorioli, L., et al. (2013). Extensive genetic engineering of hematopoiesis with therapeutic benefit in
68
EUROPEAN COMMISSION PROJECT SUMMARIES
metachromatic leukodystrophy patients after lentiviral hematopoietic stem cells gene therapy. Science 341, 1233158. Kra¨geloh-Mann, I., Groeschel, S., Kehrer, C., et al. (2013). Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort. Bone Marrow Transplant. 48, 369–375. Matsas, R., and Baron-Van Evercooren, A. (2013). Glial cell transplantation. In Neuroglia, Section 3. Role of Glial Cells in Disease: Recovery of Neural Functions. H. Kettenman and B. Ramson, ed. (Oxford University Press, New York, NY) pp. 728–745. Regis, S., Corsolini, F., Grossi, S., et al. (2013). Restoration of the normal splicing pattern of the PLP1 gene by means of an antisense oligonucleotide directed against an exonic mutation. PloS One 8, e73633. von Jonquieres, G., Mersmann, N., Klugmann, C.B., et al. (2013). Glial promoter selectivity following AAV-delivery to the immature brain. PLoS One 8, e65646.
Coordinator: Catherine Vaurs-Barrie`re, catherine [email protected] Partners: The LeukoTreat consortium brought together 23 partners from 8 countries. Catherine Vaurs-Barrie`re, Universite´ d’Auvergne Clermont-Ferrand 1, France. Enrico Bertini, Ospedale Pediatrico Bambino Gesu, Italy. Mirella Filocamo, Istituto Giannina Gaslini, Italy. Volkmar Gieselmann, Universitaetsklinikum Bonn, Germany. Patrick Aubourg, Institut National de la Sante´ et de la Recherche Me´dicale, France. Yann Dantal, Soluscience SA, France. Graham David Pavitt, University of Manchester, United Kingdom. Aurora Pujol, Fundacio privada institut d’investigacio biomedica de Bellvitge, Spain.
Klaus-Armin Nave, Max Planck gesellschaft zur foerderung der wissenschaften e.v., Germany. Johannes Berger, Medizinische Universitaet Wien, Austria. Thierry Bordet, Trophos SA, France. David Attwell, University College London, United Kingdom. Alessandra Biffi, Fondazione Centro San Raffaele del Monte Tabor/Fondazione Centro San Raffaele, Italy. Ronald Wanders, Academisch Medisch Centrum, The Netherlands. Gre´goire Moutel, Universite´ Paris Descartes, France. Olivier Degrand, France Europe innovation, France. Guy Alba, Association Europe´enne Contre Les Leucodystrophies, France. Ragnhildur Karadottir, The University of Cambridge, United Kingdom. Odile Bloespflug-Tanguy, Universite´ Paris Diderot— Paris 7, France. Graziela Uziel, Fondazione IRCCS Istituto neurologico Carlo Besta, Italy. Matthias Klugmann, University of New South Wales, Australia. Alfried Kohlschu¨tter, Universitaetsklinikum HamburgEppendorf, Germany. Ingeborg Kra¨geloh-Mann, Eberhard Karls Universitaet Tuebingen, Germany. Website: www.leukotreat.eu Disclaimer
The views expressed in this publication are the sole responsibility of the authors and do not necessarily reflect the official position of the European Commission. Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use that might be made of the information contained in this article.
DOI: 10.1089/humc.2014.2510
Optimization of Stem Cell Therapy for Clinical Trials of Degenerative Skin and Muscle Diseases (OptiStem) Contract No.: 223098; EC contribution: e 11,992,312; Total costs: e 16,564,311.99; Starting date: 01/01/2009; Duration: 60 months
Background and Objectives
Approach and Methodology
T
Epithelial and muscle stem cells were studied through ‘‘omics’’ and functional approaches in vitro, and their lineage was traced in vivo. In addition, stem cell transplantation was analyzed for integration in the diseased tissues, aiming at enhancing engraftment (through enhancing angiogenesis, migration, etc.) and at reducing inflammation and sclerosis that rather hamper their engraftment. First-inhuman clinical trials were started and completed within this network and results have been and are being published.
he overall objective of OptiStem was to integrate a large number of research groups operating at basic, translational, and clinical level on epithelia and skeletal muscle and their disease. Tissue-specific adult stem cells were studied in relation to their basic biology and their potential to treat genetic and acquired diseases of these tissues in small and large preclinical models and in patients. Stem cells were genetically corrected by different tools, mainly in preclinical animal models.
