NeuroStemCell

European Consortium for Stem Cell Therapy in Neurodegenerative Desease

Principal Investigators

Milano University, Italy

Prof.Elena CattaneoProf. Elena Cattaneo, PhD
Director of Centre for Stem Cell Research, University of Milan.

Role in the Project

The Cattaneo group will be involved in WP1 and WP2 for the neural stem (NS) cell propagation and implementation in order to produce authentic striatal GABAergic neurons that will be evaluated in transplantation experiments in HD animal models. The group will focus on the identification of the specific set of genes  that defines the optimal cell stage/graft outcome for HD and will create a number of engineered mouse and  human NS cell lines (from ES and iPS cells) with the final goal of identifying extrinsic regulators to be applied to the human lines. In the  context of WP3 and WP4 the group will perform transplantation studies to verify the efficacy of the newly derived stem cell lines and progeny.

Expertise & Competence

The main focus of this group is on the biology of the neural stem cells derived from the developing and mature brain as well as from ES and iPS cells from mouse and human. Expertise is in the propagation and neuronal differentiation of stem cell populations. These activities are oriented toward the identification of genes and soluble factors that instruct these cells to undergo division or neuronal (striatal) versus glial differentiation, with a past emphasis on the role of specific signalling molecules. In parallel the group has experience and knowledge in the study of the mechanisms   underlying Huntington’s Disease and on the epigenetic changes that occur in the disease state as well as the potential application of stem cell technologies in transplantation paradigms.

Lund University, Sweden

Prof. Anders BjörklundDr. Malin ParmarPrincipal Investigator: Prof. Anders Björklund, Professor, MD,PhD
Head of Neurobiology 

Co-Principal Investigator: Dr. Malin Parmar, Associate professor

Role in the Project

Anders Björklund is deputy coordinator of the NEuroStemCell project and Malin Parmar assist in drafting the proposal. The Björklund and Parmar research groups will contribute extensively to WP 1, 2 and 3towards the efforts to generate pure populations of cells to be used in cell replacement therapy for PD , towards establishing safe methods of grafting cells that survive long term, correct motor deficits in the absence of tumor formation and towards directed differentiation of dopamine neurons from stem cells.

Expertise & Competence

The Björklund laboratory has a leading international role in neural transplantation and pionered cell transplantation strategies for PD. The Björklund lab has during the last years provided fundamental work in areas such as transplantation, development of dopamine neurons, characterization of stem and progenitor cells in the developing fore and midbrain and generation of dopamine cells from stem cells.

Lund University, Sweden

Prof.Olle LindvallGöran HermerénPrincipal Investigator: Olle Lindvall, Professor, Head of Neurology
Co-Principal Investigator: Göran Hermerén, Professor of Medical Ethics

Role in the Project

Olle Lindvall is leader of WP6 and his laboratory will also contribute to WP3 with electrophysiological analysis of stem cell-derived neurons. Göran Hermerén will direct the work on task 6.3 and plan the workshop together with Kristina Hug and Nils-Eric Sahlin.

Expertise & Competence

Lindvall’s laboratory is at the international frontline in research on stem cell transplantation and endogenous neurogenesis after insults to the CNS. He has been leading the program which has pioneered the use of cell replacement to restore function in the diseased human brain. Hermerén is Professor of Medical Ethics since 1991 and has since many years worked in national and international ethical advisory groups.

University of Bonn, Germany

Prof. Oliver BrüstlePrincipal Investigator Prof. Oliver Brüstle, MD – Head of the Institute of Reconstructive Neurobiology, licensed neuropathologist

Role in the Project

Based on its expertise in human ES cell engineering, neural differentiation and transplantation, Partner 3 will contribute both to the generation of human ES cell-derived neural donor cells and the development of optimized transplantation paradigms. Specifically, Partner 3 will generate striatal GABAergic and mesencephalic dopaminergic cells from human ES cells (WP1). Modulation of donor cell maturation will be used to enhance migration, incorporation and axonal integration of transplanted cells (WP2 and 3).

Expertise & Competence

The major focus of the Bonn group is the use of ES cells for neural repair. The team has established protocols for controlled derivation of various neural cell types from ES cells (ref 1,2,5) and novel technologies for stem cell engineering. An important focus of the group is the functional assessment of stem cell transplants . The lab has a special interest in the differentiation and genetic modification of human ES cells.

Karolinska Institutet, Sweden

Prof.Ernest ArenasPrincipal investigator: Ernest Arenas. Professor, group leader

Role in the Project

Ernest Arenas is coordinator of WP2 and the Technology Evaluation Pannel. The group will focus on the development of novel protocols for the dopaminergic (DA) differentiation of human ES and neural stem cells (NSCs) by applying soluble factors of the Wnt family (WP1). Successful cells will be further characterized histologically and functionally in vivo, in WP2 and WP3. The group will also participate in WP5 (safety). Our goal will be to develop protocols for the safe and functional integration of human stem cells in animal models of Parkinson’s disease (PD).

Expertise & Competence

Our group has been interested in regeneration, cell engineering and cell transplantation since 1992. Our aim is to develop both neuroprotective and stem cell replacement therapies for PD (Arenas and Persson Nature 1993, Arenas et al., Neuron 1995; Trupp et al., Nature 1996; Akerud et al., J Neurosci 2001). Our strategy consists on first investigate DA neuron development, and then, apply that knowledge to differentiate ES and NSCs into DA neurons. We have previously found that overexpression of the nuclear receptor Nurr1 increases DA differentiation in NSCs (Wagner et al., Nature Biotech 1999) by activating several downstream target genes (Sousa et al., Stem cells, 2007). We also found that that neurogenin2 is required for DA neurogenesis (Kele et al., Development 2006).
More recently, we focused on the function of cell extrinsic factors in DA neuron development, such as: (i) Ligands of Nuclear receptors (Wallen et al., Genes and Dev. 2004). (ii) Wnts (Castelo-Branco et al., PNAS 2003 and JCS 2004; Prakash et al., Development 2006; Bryja et al., JCS and PNAS 2007, EMBO Report and MBC 2008, Andersson et al., PloS ONE 2008). Our current main focus is the development of protocols for: (i) The DA differentiation of ES cells without genetic modification (Sousa et al., submitted). (ii) The transplantation of stem cells in animal models of PD (Parish et al., J Clin Invest. 2008).

Karolinska Institutet, Sweden

Prof.Thomas PerlmannProf.Johan EricsonPrincipal Investigator: Thomas Perlmann, Professor
Co-Principal Investigator: Johan Ericson, Professor, Karolinska Institutet

Role in the Project

The Perlmann and Ericson groups will play equally important roles in the project and they will contribute extensively to WP 1 and 2 of this proposal. The major efforts will be devoted to the development of accurately defined mesDA neurons from human and mouse embryonic stem cells. The labs will also work to establish methods for effective and safe transplantation of stem cells in rodent Parkinson’s disease models. Moreover, the groups will further define the relevant developmental pathways of critical importance for stem cell differentiation into authentic mesDA neurons.

Expertise & Competence

Thomas Perlmann is a leading expert in the area of nuclear receptor signaling and development. The Perlmann laboratory has since long been focusing on the development of mesDA neurons and defined key pathways whereby these cells develop. The group identified Nurr1 as a critical transcription factor in the differentiation of mesDA neurons. Johan Ericson is a world leading scientist in the area of neurdevelopment. Since a few years, their work has also focused on defining key pathways important for the initial specification of mesDA neurons in
vivo and in embryonic stem cells.

University of Cardiff, United Kingdom

Stephen DunnettPrincipal investigator: Stephen Dunnett, DSc, Principal Investigator

Role in the Project

The Dunnett group will take the lead in WP3(A) to provide standardisation of simple tests of motor function for use by all groups for screening stem cell grafts, and provide the more sophisticated motor and cognitive characterisation of functional efficacy of lead candidate stem cell transplants in vivo in animal models of both Huntington’s and Parkinson’s diseases. We will contribute to the in vivo imaging of behaviourally characterised stem cell transplants in WP3(B) under the leadership of partner 6.

Expertise & Competence

The Brain Repair Group in the Cardiff School of Biosciences is a multidisciplinary team of 30 postdoctoral scientists, technicians and students, co-directed by SBD as the basic behavioural neuroscientist and my clinician scientist colleague Prof Anne Rosser, with the mission to develop cell based therapies for application in human neurodegenerative disease. To this end, the BRG adopts an integrated research programme spanning basic and translational cell and molecular science, development of animal models of human neurodegenerative disease and cell transplantation methods, alongside the analytical behavioural analysis of motor and cognitive functions to assess disability and repair in animals and man. Our specific expertise, for which we have an international reputation, lies in the assessment of motor and cognitive function associated with cell transplantation in animal models of Huntington’s and Parkinson’s diseases.

CEA, France

Philippe HantrayePrincipal Investigator: Philippe Hantraye, PhD, Head of the Molecular Imaging Research Center (MIRCen)

Role in the Project

The CEA group will extensively contribute to WP4 aiming at assessing long-term function of grafted cells with imaging.

Expertise & Competence

The Hantraye group has a long lasting pre-clinical and clinical experience in neurodegenerative diseases. It played a pioneer role in the development and validation of therapeutic strategies for PD and HD, including fetal graft and high field cortical stimulation. The team has also an extensive experience in the development of stateof- the-art imaging methods (PET, MRI or MRS) dedicated to the monitoring of brain functions in living beings (including non-human and human primates).

University of Cambridge

Austin SmithRoger A BarkerPrincipal Investigators: Austin Smith PhD FRS – Director, Wellcome Trust Centre for Stem Cell Research
Roger A Barker Phd MRCP – Reader in Clinical Neuroscience and Honorary Consultant in Neurology.

Role in the Project

The Smith group will contribute extensively to WP1 and 2 and play a role in stability studies in WP5. The group will focus on optimal conditions for production and stable expansion of neural stem cells from ES cells and foetal tissue sources and on the generation of mesDA and striatal GABAergic neurons under direction of extrinsic regulators. The group will provide to the consortium recently derived rat ES cells and rat NS cells, in addition to human NS cells.
The Barker group will contribute to WP6, namely the clinical translation of stem cell therapies to patients with Parkinson’s disease. The group will focus on defining subtypes of PD, and their basis such that novel therapies can best be targeted to appropriate groups of patients. In addition, novel objective markers of disease will be employed to better quantify therapeutic effects of any such translational stem cell therapies.

Expertise & Competence

The Smith laboratory pioneered molecular studies in embryonic stem cell biology, discovering the roles of extrinsic signals LIF and BMP and of intrinsic transcriptional organizers Oct4 and Nanog. The laboratory has defined the central roles of FGF4 and Notch signaling in ES cell commitment to neural lineages. Recently the group has established defined conditions for propagation of pluripotent stem cells by inhibition of the Ras/Erk pathway in combination with suppression of GSK3 activity. These conditions
have enabled for the first time derivation of authentic rat ES cells. Smith and colleagues also developed adherent neural stem (NS) cell cultures in collaboration with Elena Cattaneo and the group has isolated multiple NS cell lines from mouse, rat and human sources.
The Barker group has identified putative sub-sets of Parkinson’s disease with distinct neurological and clinical features, which have different prognoses, biomarker profiles  and  genetic risk factors. We have identified critical clinical and genetic predictors of cognitive change in PD, as well as identifying groups of patients who would do best with cell therapies. In addition we have been the main surgical and assessment centre in a UK transplant trial involving patients with mild-moderate Huntington’s Disease who have been grafted with fetal striatal allografts.

INSERM, France

Anselme PerrierMarc PeschanskiPrincipal Investigator : Anselme Perrier, PhD, chargé de recherche INSERM
Co-Principal Investigator : Marc Peschanski, MD PhD, directeur de recherche INSERM

Role in the Project

The I-STEM team is dedicated to setting up intracerebral transplantation for Huntington disease. This implies its participation to all HD specific steps in the program, from the basic requirements in terms of protocols of differentiation and cell production, up to the follow up of intracerebral grafts in animals and design of safety procedures for clinical use, with particular reference to the use of human embryonic stem cells. The I-STEM team will, therefore, be part of WP1 for delivering engineered embryonic stem cell lines
allowing the identification and sorting of striatal neurons, WP2 for protocols of striatal differentiation and comparison of the striatal progeny of cell lines, as well as the evaluation of the safety switch engineered in human ES cells, and in the final WP6 reporting.

Expertise & Competence

INSERM U 861 (I-STEM) has been created in 2005 as a continuation of the translational research previously performed in another Unit by Marc Peschanski and his team, that had led to the pioneer demonstration of the clinical improvement provided by intracerebral cell therapy to patients with Huntington disease. The I-STEM “neurodegenerative diseases” team, led by Anselme Perrier, is dedicated to the development of a new source of cells to replace the currently used foetal tissue, to be used in this clinical indication. It aims currently at using the striatal neuronal progeny of human embryonic stem cells for those purposes.

INSERM, France

Anne-Catherine Bachoud-LéviPrincipal investigator: Anne-Catherine Bachoud-Lévi, MD

Role in the Project

The INSERM E1 group will extensively contribute to WP6 aiming to prepare clinical application of stem cells in HD both for the ethical side and the clinical side.

Expertise & Competence

The INSERM U841 team 1group has a long lasting clinical experience in HD. ACBL is currently coordinating the Huntington French Speaking Group, is one of the member of the executive committee of the EHDN (European Huntington’s disease network) and she’s coordinating the multicentre trial including 60 HD patients among France and Belgium for intracerebral grafting using human fetal cells and the national center for HD thanks to the French Ministry of Health. Patrick Maison is keen in methodology of transplant trials.The team has also an extensive experience in the development of state-of-the-art of longitudinal follow-up and more specifically in cognitive testing dedicated to the monitoring of brain functions in HD patients.

Imperial College London, Clinical Science Centre, UK

Dr. Meng Li Principal Investigator: Dr. Meng Li – Principal Investigator, Group leader

Role in the Project

Dr. Meng Li – Generation of defined population of mesencephalic dopaminergic neurons, progenitors, transplantation and evaluation of survival, differentiation and integration of stem cell derivatives; contributor of WP1 and WP2. Dr. Mark Ungless – Physiology of neural stem cell derived dopaminergic neurons, transplantation of neuralized ES cells and NS cells. The Li group interacts closely with Malin Parmar and Anders Bjorklund on FoxP1 related project and with Austin Smith on projects involving directed differentiation into neurones of ES cells.

Expertise & Competence

Dr. Li has long standing interest in neural specification in embryonic stem cells and has pioneered Sox gene based lineage selection allowing the marking and isolation of neural progenitors and stem cells from heterogeneous ES cell differentiated progeny. The group’s expertises are neural differentiation of ES cells and genetic manipulation of ES cells including homologous recombination and transgene expression. Dr. Ungless has broad electrophysiological experience, particularly with midbrain dopamine neurons. His group conducts in vivo and in vitro electrophysiological recordings from dopamine neurons, combined with single-cell labelling and neuroanatomical analysis.

BioRep SrL, Italy

Principal Investigator: Ida Biunno, Scientific Director of BioRep and Senior researcher at Institute of Biomedical Technologies of the National Research Council in Milan

Role in the Project

Ida Biunno is the scientific director of BioRep, she directs the scientific programs held in the laboratories. In Neurostem she will be involved in the systematic assessment of the genomic stability neuronal derived stem cell for the entire consortium. For the purpose she will use the following technologies: SNPs analysis, spectral karyotyping (to detect gross chromosomal alterations) and comparative genomic hybridisation (CGH) to detect small genomic variations which may occur over culturing or in the overall processing of the cell lines.

Expertise & Competence

BioRep personell consists of researchers, technicians and PhD students working in cell and molecular biology as well as functional genomics. BioRep provides a variety of molecular and cell biology basic services, microbiology and epigenetic and cytogenetic public and private research institutions.

NsGene A/S, Denmark

Lars U. WahlbergDr. Bengt JuliussonPrincipal Investigator: Lars U. Wahlberg, Exec. VP & COO
Co-Principal Investigator: Dr. Bengt Juliusson, Head of Quality Assurance and Regulatory Affairs – Regulatory and quality issues in manufacturing, testing, and human translation of stem-cell based therapies; Evaluation of tomato thymidine kinase suicide system as safety switch.

Role in the Project

NsGene owns intellectual property on NS cells, cell sorting markers, and novel growth factors applicable to cell development and differentiation of stem cells for PD and HD. This work and reagents will be applied to WP1. In addition, NsGene owns rights to a modified tomato kinase suicide system applicable as safety switch to transplanted cells that will be evaluated in WP2. Last, the company develops a clinically applicable delivery system (ECB) suitable for short or long-term in situ delivery of graft-supporting growth factors such as GDNF to promote the survival and functional integration of transplanted cells. This will be tested in WP3. In WP6, NsGene’s experiencee with manufacturing, quality assurance, and clinical trials with cell-based therapies will be applied to the cell selection and testing protocols

Expertise & Competence

The Company has been working with human neural stem cells, gene therapy, the ECB technology, novel protein factors, and expression vectors since its inception in 1999. Dr. Wahlberg is a co-inventor of the ECB technology, NS cells, and Meteorin and other novel growth factors utilized in the proposed work.

Sloan-Kettering Institute, United States

Dr. Lorenz StuderPrincipal Investigator: Lorenz Studer, MD

Role in the Project

Dr. Lorenz Studer at Sloan-Kettering in New York is leading the development of a new technology using so-called BAC-constructs to generate with high efficiency human ES cells that express cellular labels, such as the green-fluorescent protein, GFP, under cell stage-specific promoters, which allows the identification and isolation of dopamine and striatal neuronal precursors at specific stages of differentiation. Dr. Studer will add new efforts in the generation of transplantable DA and striatal Gabaergic neurons. The addition of his new BAC-technology would undoubtedly facilitate the development of new cell lines.

Expertise & Competence

Dr. Studer’s laboratory aims at exploiting recent advances in stem cell biology to develop radically new therapies for degenerative disease and cancer, working with both embryonic and adult stem cell types. However, the main current focus is on the biology and use of human embryonic stem cells. A major effort of the lab is devoted to harnessing and manipulating the differentiation potential of embryonic stem cells towards specific brain cell population in vitro. The Lab is also interested in applications outside the CNS particularly in musculoskeletal disease. Probing into the molecular signals required for converting stem cells into specialized cell types in a culture dish will also provide novel insights into basic mechanisms of development. The lab is developing high throughput chemical and genetic screens to systematically address such questions in human embryonic stem cells.

Back to top page