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PROMETHEUS: Pluripotent Stem Cells for Therapy of Parkinson’s Disease - a multidisciplinary and translational consortium

English title PROMETHEUS: Pluripotent Stem Cells for Therapy of Parkinson’s Disease - a multidisciplinary and translational consortium
Applicant Krause Karl-Heinz
Number 125408
Funding scheme Sinergia
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurology, Psychiatry
Start/End 01.04.2009 - 31.03.2014
Approved amount 2'100'000.00
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Keywords (6)

preclinical; cell therapy; Parkinson's disease; embryonic stem cells; dopaminergic neurson; safety

Lay Summary (English)

Lead
Lay summary
Parkinson's disease (PD) is a devastating neurodegenerative disease. The main symptoms of the patient are linked to mobility and the term "shaking palsy" is also used for the disease. Available treatment for Parkinson's disease are capable of improving symptoms for a limited period of time, but presently no cure is available. The cause of Parkinson's disease is the loss of a certain type of nerve cells in the brain, in particular the so-called "dopaminergic neurons. It is the long term aim of our project to implant dopaminergic neurons, generated from embryonic stem cells, into damaged brain areas of patients with Parkinson's disease. The PROMETHEUS consortium proposes to address key issues for a successful transfer of the concept into clinical studies. Six different groups will work together synergistically to i) optimize production of dopaminergic neurons from embryonic stem cells, ii) to test these cells as therapeutics in animal models, iii) to develop strategies that minimize the risk or tumor formation from implanted cells, iv) to develop strategies to avoid immune rejection, v) to follow a patient cohort in preparation of a first clinical study, and vi) to analyze ethical issues concerning all aspects of the proposal (stem cell generation, animal experimentation and first patient studies). If successful, the PROMETHEUS consortium should provide important new tools for the treatment of Parkinson's disease
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The Role of Immunosuppression in the Transplantation of Allogenic Neural Precursors Derived from Human Pluripotent Stem Cells for Parkinson’s Disease
Casimir de Rham, Tieng Vannary, Tournier Benjamin, Avila Yannick, Ginovart Nathalie, Krause Karl-heinz, Preynat-Seauve Olivier, Dubois-Dauphin Michel, Villard Jean (2014), The Role of Immunosuppression in the Transplantation of Allogenic Neural Precursors Derived from Human Pluripotent Stem Cells for Parkinson’s Disease, in Stem Cell Research & Therapy, 1-9.
Variability of manual dexterity performance in non-human primates (Macaca fascicularis)
Kaeser Mélanie, Chatagny Pauline, Gindrat Anne-Dominique, Savidan Julie, Badoud Simon, Fregosi Michela, Moret Véronique, Roulin Christine, Rouiller Eric M, Schmidlin Eric (2014), Variability of manual dexterity performance in non-human primates (Macaca fascicularis), International Journal of Comparative Psychology, USA.
Whole-scalp EEG mapping of somatosensory evoked potentials in macaque monkeys.
Gindrat Anne-Dominique, Quairiaux Charles, Britz Juliane, Brunet Denis, Lanz Florian, Michel Christoph M, Rouiller Eric M (2014), Whole-scalp EEG mapping of somatosensory evoked potentials in macaque monkeys., in Brain structure & function, May 4. [Epub ahead of print] PubMed PMID: 24791748, 1-22.
Distinction between hand dominance and hand preference in primates: a behavioral investigation of manual dexterity in nonhuman primates (macaques) and human subjects.
Chatagny Pauline, Badoud Simon, Kaeser Mélanie, Gindrat Anne-Dominique, Savidan Julie, Fregosi Michela, Moret Véronique, Roulin Christine, Schmidlin Eric, Rouiller Eric M (2013), Distinction between hand dominance and hand preference in primates: a behavioral investigation of manual dexterity in nonhuman primates (macaques) and human subjects., in Brain and behavior, 3(5), 575-95.
Involuntary & Voluntary Invasice Brain Surgery : Ethical Issues Related to Acquired aggressiveness.
Gilbert F, Vranic A, Hurst SA (2013), Involuntary & Voluntary Invasice Brain Surgery : Ethical Issues Related to Acquired aggressiveness., in Neuroethics, 6( 1), 115-128.
Cellular diversity within embryonic stem cells: Pluripotent clonal sublines show distinct differentiation potential
Martinez Y, Béna F, Gimelli S, Tirefort D, Dubois-Dauphin M, Krause K-H, Preynat-Seauve O (2012), Cellular diversity within embryonic stem cells: Pluripotent clonal sublines show distinct differentiation potential, in Journal of Cellular and Molecular Medicine, 16(3), 456-467.
Clinically Driven Safety Benchmarks
Barazzetti G, Hurst SA, Mauron A (2012), Clinically Driven Safety Benchmarks, in AJOB Neuroscience, 3(2), 22-23.
Generation and applications of human pluripotent stem cells induced into neural lineages and neural tissues
Martinez Yannick, Dubois-Dauphin Michel, Krause Karl-Heinz (2012), Generation and applications of human pluripotent stem cells induced into neural lineages and neural tissues, in Frontiers in Physiology, 3 MAR, 3-47.
Haplotype-based banking of human pluripotent stem cells for transplantation: Potential and limitations
Zimmermann A, Preynat-Seauve O, Tiercy J-M, Krause K-H, Villard J (2012), Haplotype-based banking of human pluripotent stem cells for transplantation: Potential and limitations, in Stem Cells and Development, 21(13), 2364-2373.
How to cross immunogenetic hurdles to human embryonic stem cell transplantation.
de Rham Casimir, Villard Jean (2011), How to cross immunogenetic hurdles to human embryonic stem cell transplantation., in Seminars in immunopathology, 33(6), 525-34.
Stem cell sources for regenerative medicine: The immunological point of view
Preynat-Seauve O, Krause K-H (2011), Stem cell sources for regenerative medicine: The immunological point of view, in Seminars in Immunopathology, 33(6), 519-524.
Isoform- and dose-sensitive feedback interactions between paired box 6 gene and δ-catenin in cell differentiation and death
Zhang J, Lu J-P, Suter DM, Krause K-H, Fini ME, Chen B, Lu Q (2010), Isoform- and dose-sensitive feedback interactions between paired box 6 gene and δ-catenin in cell differentiation and death, in Experimental Cell Research, 316(6), 1070-1081.
It's not who you are
Baertschi B, Hurst SA, Mauron A (2010), It's not who you are, in AJOB Neuroscience, 1(3), 18-19.
Markers of murine embryonic and neural stem cells, neurons and astrocytes : reference po0ints for developmental neurotixicity testing.
Kuegler PB, Zimmer B, Waldmann T, Baudis B, Llmjarv S, Hescheler J, Gaughwin P, Brundin P, Mundy W, Bal-Price AK, Schrattenholz A, Krause KH, Van Thriel C, Rao MS, Kadereit S, Leist M (2010), Markers of murine embryonic and neural stem cells, neurons and astrocytes : reference po0ints for developmental neurotixicity testing., in ALTEX, 27(1)(27(1)), 17-42.
Stem cell-derived neurons grafted in the striatum are expelled out of the brain after chronic cortical stroke.
Dubois-Dauphin Michel, Julien Stéphanie (2010), Stem cell-derived neurons grafted in the striatum are expelled out of the brain after chronic cortical stroke., in Stroke; a journal of cerebral circulation, 41(8), 1807-14.
The long-term survival of in vitro engineered nervous tissue derived from the specific neural differentiation of mouse embryonic stem cells.
Dubois-Dauphin Michel L, Toni Nicolas, Julien Stéphanie D, Charvet Igor, Sundstrom Lars E, Stoppini Luc (2010), The long-term survival of in vitro engineered nervous tissue derived from the specific neural differentiation of mouse embryonic stem cells., in Biomaterials, 31(27), 7032-42.
Neural progenitors derived from human embryonic stem cells are targeted by allogeneic T and natural killer cells.
Preynat-Seauve Olivier, de Rham Casimir, Tirefort Diderik, Ferrari-Lacraz Sylvie, Krause Karl-Heinz, Villard Jean (2009), Neural progenitors derived from human embryonic stem cells are targeted by allogeneic T and natural killer cells., in Journal of cellular and molecular medicine, 13(9B), 3556-69.
Phenazopyridine induces and synchronizes neuronal differentiation of embryonic stem cells
Suter DM, Preynat-Seauve O, Tirefort D, Feki A, Krause K-H (2009), Phenazopyridine induces and synchronizes neuronal differentiation of embryonic stem cells, in Journal of Cellular and Molecular Medicine, 13(9 B), 3517-3527.
Pluripotent stem cells as new drugs? The example of Parkinson's disease.
Preynat-Seauve Olivier, Burkhard Pierre R, Villard Jean, Zingg Walter, Ginovart Nathalie, Feki Anis, Dubois-Dauphin Michel, Hurst Samia A, Mauron Alex, Jaconi Marisa, Krause Karl-Heinz (2009), Pluripotent stem cells as new drugs? The example of Parkinson's disease., in International journal of pharmaceutics, 381(2), 113-21.
Engineering of Midbrain Organoids Containing Long-Lived Dopaminergic Neurons.
Tieng Vannary, Stoppini Luc, Villy Sabrina, Dubois-Dauphin Michel, krause Karl-heinz, Fathi Marc, Engineering of Midbrain Organoids Containing Long-Lived Dopaminergic Neurons., in Stem Cells Dev, Volume 00, (Number 00).

Communication with the public

Communication Title Media Place Year
Print (books, brochures, leaflets) Clinically-driven safety benchmarks. American Journal of Bioethics. 2012. in Press International 2012
New media (web, blogs, podcasts, news feeds etc.) L'expérimentation animale: une pesée en désiquilibre Bioethica Forum 2012;5(1):20-2 Western Switzerland 2012
Talks/events/exhibitions maladie de Parkinson Enjeux et Espoirs Western Switzerland 2012
Print (books, brochures, leaflets) Clinical research on conditions affecting cognition International 2011
Media relations: print media, online media Experimenting innovative Cell Therapies for Parkinson's Disease: A view from Ethics P107-122 Bielefeld: Transcript Verlag 2011 German-speaking Switzerland 2011

Associated projects

Number Title Start Funding scheme
149643 Mechanisms of motor recovery from brain lesion 01.10.2013 Project funding
132465 Mechanisms of recovery from central nervous system lesion in non-human primates 01.10.2010 Project funding
128666 Gamma Irradiator for Research in Immunology, Infectious Diseases, Stem Cell Biology, and Neurobiology 01.12.2009 R'EQUIP
128821 High-resolution ultrasound imaging for micro-targeted in vivo delivery and monitoring of cells, genes, and biomaterials. 01.12.2009 R'EQUIP

Abstract

Parkinson's disease (PD) is a devastating neurodegenerative disease. Although the neuropathology is widespread in advanced disease, the motor symptoms appear to be mostly due to the loss of dopaminergic neurons in the substantia nigra. Given the relative importance of this specific cell loss, PD is considered as a promising target for cell therapy. The potential of pluripotent stem cells, PSCs, (i.e. embryonic stem cells and - possibly on the long - run induced pluripotent stem cells) to generate high quality dopaminergic neurons in vitro and their efficiency to improve symptoms in rodent and primate models of PD has been well documented (1). However, there is a considerable gap between successful laboratory research in this domain and the progress towards a clinical application. It is the aim of the Prometheus project to bridge the gap between the present research and future applications in humans. For this purpose, close collaborations between experts from diverse areas are required: clinicians (neurologists, neurosurgeons, radiologists, immunologists, infection control experts), laboratory based researchers (animal experimentation; cell biologists), as well as biomedical ethicists. The Prometheus consortium consists of seven closely collaborating groups that will cover the major preclinical challenges of PD cell therapy. Group 1 will produce clinical grade dopaminergic neurons from human embryonic stem cells. Group 2 will test cells produced by G1 in rodent and primate models and investigate the role of PET imaging as in-vivo follow-up of transplanted cells. Group 3 will focus on strategies of tumor/teratoma prevention. Group 4 will study immune reactions towards transplanted cells and advise G2 and G6 on immunosuppressive therapies. Group 5 will coordinate infection control and quality assurance and will provide advise and microbiological testing for G1, G2 and G6. Group 6 will integrate the information received from all other groups and define base-line parameters through a pre-study follow-up of PD patients, as well as establish a clinical protocol for patient selection and determine the best neurosurgical procedure. Group 7 will work on ethical aspects of the cell and animal studies, as well as all ethical prerequisites for the initial clinical studies. The ultimate goal of the project is to advance towards a cell therapy for PD under conditions that fully integrate experimental science, patient security and biomedical ethics. Only an interdisciplinary team, such as the one assembled for this project will be able to meet this challenge. To our understanding, no such comprehensive approach to the problem is presently implemented in other places. This should give the Prometheus team a leading edge in the development of a safe and ethical development of cell therapy for PD.
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