Development of a platform to generate clinical grade neural progenitors for transplantation in Huntington's disease.

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

Human embryonic stem cells (hESCs) have recieved enormous scientific, public and media attention for their potential to develop into all cell types of the body, and thus provide an unparalleled source of cells for regenerative medicines. The neurodegenerative diseases represent a major class of diseases predicted to benefit from emerging stem cell-based therapies. Huntington?s disease (HD) is one such disorder, that in many ways represents a model disorder for the development of cell-based therapies. HD has a defined genetic basis and primarily affects a focal group of cells in the forebrain. It is anticipated that developing technologies and clinical expertise to treat HD will have wider ramifications for the potential treatment of more complex and common neurodegenrative disorders, perhaps including Alzheimer?s disease, Parkinson?s disease and Stroke.
Significant basic research has already been conducted to study the biology and potential of hESCs to generate functional neurons, but while the progress to date rightly generates considerable optimism, many technical and regulatory issues need to be addressed before this research can be considered for clinical trials. This proposal aims to take the first vital step in translating protocols from a research towards a clinical-grade platform. Specifically, we will adapt our protocols that derive neurons from hESCs that are of value to HD, to generate cells with sufficient yield and to meet regulatory standards of safety and reproducibility (i.e. to develop protocols compatible with Good Manufacturing Practice (GMP)), and most importantly cells will be tested for functional efficacy in animal models of HD.

Technical Summary

Transplantation of striatal progenitor cells that reconstitute missing DARPP-32 positive medium spiny projection neurons is a major strategy under assessment and consideration for the treatment of Huntington‘s disease (HD). The greatest single issue for development of this therapy concerns the availability of a renewable source of appropriately specified donor neural progenitor cells.
Currently, directed differentiation of human embryonic stem cells (hESCs) to neural progenitors has the greatest potential of meeting this requirement. This view is supported by key advances in basic research including, (i) progress in developing methodology for the derivation and propagation of hESC lines, and (ii) understanding of underlying mechanisms of forebrain development and neuronal sub-type specification that provide a rationale for the development of directed differentiation protocols. Critically we have now developed protocols for neural differentiation under defined conditions to generate progenitors that express markers of forebrain fate determination, and that differentiate to DARPP-32 positive neurons both in vitro and in vivo in animal models of HD.
This translational project aims to expedite the ultimate goal of bringing stem cell therapies to clinical trial by adapting, and further developing, protocols to generate cells with markedly improved yields and a level of reproducibility and quality control that meet regulatory standards of good manufacturing practice (GMP), while maintaining a high functional efficacy in vivo in animal models of HD.
 
Description ?Human pluripotent stem cell differentiation, safety and preparation for therapeutic transplantation in Huntington's disease
Amount € 6,000,000 (EUR)
Funding ID 602245 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 10/2013 
End 09/2017
 
Description CHDI Joint Steering Committee
Amount £625,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2012 
End 12/2013
 
Description CHDI project grant
Amount £350,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2010 
End 12/2012
 
Title Human ES cell neural differentiation methodology 
Description Development of chemically defined (to be GMP compliant) culture media and protocols for directed neural differentiation. Media avoid use of all animal products, and are used for efficient generationa nd expansion of neural progenitors. 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact The basic protocol is being further adapted to establish GMP compliant conditions to derive cells for neural transplantation therapies 
 
Title Improved ES cell neural differentiation 
Description Improvements have been made in the efficiency of generating transplantable neural progenitors through the use of small molecule pathway inhibitors. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Protocols are being developed to inprove potential GMP compliance for translational use of ES cells for neural transplantation. 
 
Description Clinical grade hESCs 
Organisation Roslin Cells Ltd
Country United Kingdom 
Sector Private 
PI Contribution We have begun a collaboration with Roslin Cells to evaluate one of their clinical grade hES cell lines for neural differentiation
Collaborator Contribution Provision of cell lines and know how
Impact ongoing
Start Year 2011
 
Description FP7 Repair HD 
Organisation Alternative Energies and Atomic Energy Commission (CEA)
Country France 
Sector Public 
PI Contribution We have established an EU consortium, developed from current and previous collaborations to apply for FP7 funding for a project towards the translational stem cell therapy by transplantation. EU Acronym-RepairHD Our research team (Allen/Rosser/Dunnett) have expertise in pluripotent stem cell differentiation, neural transplantation in preclinical models, and clinical neurology.
Collaborator Contribution Partners have complimentary skills Dr. Anselme Perrier- Striatal stem cell differentiation protocols in vitro molecular and cellular phenotyping. Dr. Anne-C Bachoud-Levi - Neurological/neuropsychological assessment Dr. Philippe Hantraye - Primate neurobiology transplantation and function, In vivo PET and MRI imaging; inflammation Dr. Emanuele Cozzi - Human xenograft Immunosuppression in primates Mr Kevin Bruce- hES culturing and handling, hIPSC derivation and characterisation; GMP; cell banking; regulatory compliance Dr. David Craufurd- Neuropsychiatry; clinical trial design and assessment Dr. med. Ralf Reilmann- Clinical and experimental neurology; Clinical training and assessment
Impact Application to FP7-HEALTH-2013-INNOVATION -Call 1HEALTH.2013.1.4-1 Multidisciplinary
Start Year 2012
 
Description FP7 Repair HD 
Organisation National Institute of Health and Medical Research (INSERM)
Department Inserm Transfert
Country France 
Sector Public 
PI Contribution We have established an EU consortium, developed from current and previous collaborations to apply for FP7 funding for a project towards the translational stem cell therapy by transplantation. EU Acronym-RepairHD Our research team (Allen/Rosser/Dunnett) have expertise in pluripotent stem cell differentiation, neural transplantation in preclinical models, and clinical neurology.
Collaborator Contribution Partners have complimentary skills Dr. Anselme Perrier- Striatal stem cell differentiation protocols in vitro molecular and cellular phenotyping. Dr. Anne-C Bachoud-Levi - Neurological/neuropsychological assessment Dr. Philippe Hantraye - Primate neurobiology transplantation and function, In vivo PET and MRI imaging; inflammation Dr. Emanuele Cozzi - Human xenograft Immunosuppression in primates Mr Kevin Bruce- hES culturing and handling, hIPSC derivation and characterisation; GMP; cell banking; regulatory compliance Dr. David Craufurd- Neuropsychiatry; clinical trial design and assessment Dr. med. Ralf Reilmann- Clinical and experimental neurology; Clinical training and assessment
Impact Application to FP7-HEALTH-2013-INNOVATION -Call 1HEALTH.2013.1.4-1 Multidisciplinary
Start Year 2012
 
Description FP7 Repair HD 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Academic/University 
PI Contribution We have established an EU consortium, developed from current and previous collaborations to apply for FP7 funding for a project towards the translational stem cell therapy by transplantation. EU Acronym-RepairHD Our research team (Allen/Rosser/Dunnett) have expertise in pluripotent stem cell differentiation, neural transplantation in preclinical models, and clinical neurology.
Collaborator Contribution Partners have complimentary skills Dr. Anselme Perrier- Striatal stem cell differentiation protocols in vitro molecular and cellular phenotyping. Dr. Anne-C Bachoud-Levi - Neurological/neuropsychological assessment Dr. Philippe Hantraye - Primate neurobiology transplantation and function, In vivo PET and MRI imaging; inflammation Dr. Emanuele Cozzi - Human xenograft Immunosuppression in primates Mr Kevin Bruce- hES culturing and handling, hIPSC derivation and characterisation; GMP; cell banking; regulatory compliance Dr. David Craufurd- Neuropsychiatry; clinical trial design and assessment Dr. med. Ralf Reilmann- Clinical and experimental neurology; Clinical training and assessment
Impact Application to FP7-HEALTH-2013-INNOVATION -Call 1HEALTH.2013.1.4-1 Multidisciplinary
Start Year 2012
 
Description FP7 Repair HD 
Organisation Organ Donation Research Consortium (ODRC)
Country Global 
Sector Charity/Non Profit 
PI Contribution We have established an EU consortium, developed from current and previous collaborations to apply for FP7 funding for a project towards the translational stem cell therapy by transplantation. EU Acronym-RepairHD Our research team (Allen/Rosser/Dunnett) have expertise in pluripotent stem cell differentiation, neural transplantation in preclinical models, and clinical neurology.
Collaborator Contribution Partners have complimentary skills Dr. Anselme Perrier- Striatal stem cell differentiation protocols in vitro molecular and cellular phenotyping. Dr. Anne-C Bachoud-Levi - Neurological/neuropsychological assessment Dr. Philippe Hantraye - Primate neurobiology transplantation and function, In vivo PET and MRI imaging; inflammation Dr. Emanuele Cozzi - Human xenograft Immunosuppression in primates Mr Kevin Bruce- hES culturing and handling, hIPSC derivation and characterisation; GMP; cell banking; regulatory compliance Dr. David Craufurd- Neuropsychiatry; clinical trial design and assessment Dr. med. Ralf Reilmann- Clinical and experimental neurology; Clinical training and assessment
Impact Application to FP7-HEALTH-2013-INNOVATION -Call 1HEALTH.2013.1.4-1 Multidisciplinary
Start Year 2012
 
Description FP7 Repair HD 
Organisation Roslin Cellab
Country United Kingdom 
Sector Private 
PI Contribution We have established an EU consortium, developed from current and previous collaborations to apply for FP7 funding for a project towards the translational stem cell therapy by transplantation. EU Acronym-RepairHD Our research team (Allen/Rosser/Dunnett) have expertise in pluripotent stem cell differentiation, neural transplantation in preclinical models, and clinical neurology.
Collaborator Contribution Partners have complimentary skills Dr. Anselme Perrier- Striatal stem cell differentiation protocols in vitro molecular and cellular phenotyping. Dr. Anne-C Bachoud-Levi - Neurological/neuropsychological assessment Dr. Philippe Hantraye - Primate neurobiology transplantation and function, In vivo PET and MRI imaging; inflammation Dr. Emanuele Cozzi - Human xenograft Immunosuppression in primates Mr Kevin Bruce- hES culturing and handling, hIPSC derivation and characterisation; GMP; cell banking; regulatory compliance Dr. David Craufurd- Neuropsychiatry; clinical trial design and assessment Dr. med. Ralf Reilmann- Clinical and experimental neurology; Clinical training and assessment
Impact Application to FP7-HEALTH-2013-INNOVATION -Call 1HEALTH.2013.1.4-1 Multidisciplinary
Start Year 2012
 
Description FP7 Repair HD 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution We have established an EU consortium, developed from current and previous collaborations to apply for FP7 funding for a project towards the translational stem cell therapy by transplantation. EU Acronym-RepairHD Our research team (Allen/Rosser/Dunnett) have expertise in pluripotent stem cell differentiation, neural transplantation in preclinical models, and clinical neurology.
Collaborator Contribution Partners have complimentary skills Dr. Anselme Perrier- Striatal stem cell differentiation protocols in vitro molecular and cellular phenotyping. Dr. Anne-C Bachoud-Levi - Neurological/neuropsychological assessment Dr. Philippe Hantraye - Primate neurobiology transplantation and function, In vivo PET and MRI imaging; inflammation Dr. Emanuele Cozzi - Human xenograft Immunosuppression in primates Mr Kevin Bruce- hES culturing and handling, hIPSC derivation and characterisation; GMP; cell banking; regulatory compliance Dr. David Craufurd- Neuropsychiatry; clinical trial design and assessment Dr. med. Ralf Reilmann- Clinical and experimental neurology; Clinical training and assessment
Impact Application to FP7-HEALTH-2013-INNOVATION -Call 1HEALTH.2013.1.4-1 Multidisciplinary
Start Year 2012
 
Description FP7 Repair HD 
Organisation University of Münster
Country Germany 
Sector Academic/University 
PI Contribution We have established an EU consortium, developed from current and previous collaborations to apply for FP7 funding for a project towards the translational stem cell therapy by transplantation. EU Acronym-RepairHD Our research team (Allen/Rosser/Dunnett) have expertise in pluripotent stem cell differentiation, neural transplantation in preclinical models, and clinical neurology.
Collaborator Contribution Partners have complimentary skills Dr. Anselme Perrier- Striatal stem cell differentiation protocols in vitro molecular and cellular phenotyping. Dr. Anne-C Bachoud-Levi - Neurological/neuropsychological assessment Dr. Philippe Hantraye - Primate neurobiology transplantation and function, In vivo PET and MRI imaging; inflammation Dr. Emanuele Cozzi - Human xenograft Immunosuppression in primates Mr Kevin Bruce- hES culturing and handling, hIPSC derivation and characterisation; GMP; cell banking; regulatory compliance Dr. David Craufurd- Neuropsychiatry; clinical trial design and assessment Dr. med. Ralf Reilmann- Clinical and experimental neurology; Clinical training and assessment
Impact Application to FP7-HEALTH-2013-INNOVATION -Call 1HEALTH.2013.1.4-1 Multidisciplinary
Start Year 2012
 
Description HD iPS Consortium 
Organisation CHDI Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution Development of HD iPS consortium, HD iPS cell neuronal differentiation and characteristion of disease phenotype. Electrophysiological studies
Collaborator Contribution Cedars Sinai, Svendsen Lab- HDiPS derivation phenotyping Irvive, Thompson Lab- Transcriptomics Johns Hopkins, Ross Lab, Proteomics, neurodegeneration phenotyping Gladstone, Finkbeiner lab-High content neuronal imaging/phenotyping Milan, Cattaneo lab-cell differentiation Harvard, MacDonald Gusella lab-HD genetics, metabolomics
Impact HD iPS consortium publication in Cell Stem Cell Conference procedings Resaerch seminars
Start Year 2010
 
Description HD iPS Consortium 
Organisation Cedars-Sinai Medical Center
Country United States 
Sector Hospitals 
PI Contribution Development of HD iPS consortium, HD iPS cell neuronal differentiation and characteristion of disease phenotype. Electrophysiological studies
Collaborator Contribution Cedars Sinai, Svendsen Lab- HDiPS derivation phenotyping Irvive, Thompson Lab- Transcriptomics Johns Hopkins, Ross Lab, Proteomics, neurodegeneration phenotyping Gladstone, Finkbeiner lab-High content neuronal imaging/phenotyping Milan, Cattaneo lab-cell differentiation Harvard, MacDonald Gusella lab-HD genetics, metabolomics
Impact HD iPS consortium publication in Cell Stem Cell Conference procedings Resaerch seminars
Start Year 2010
 
Description HD iPS Consortium 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution Development of HD iPS consortium, HD iPS cell neuronal differentiation and characteristion of disease phenotype. Electrophysiological studies
Collaborator Contribution Cedars Sinai, Svendsen Lab- HDiPS derivation phenotyping Irvive, Thompson Lab- Transcriptomics Johns Hopkins, Ross Lab, Proteomics, neurodegeneration phenotyping Gladstone, Finkbeiner lab-High content neuronal imaging/phenotyping Milan, Cattaneo lab-cell differentiation Harvard, MacDonald Gusella lab-HD genetics, metabolomics
Impact HD iPS consortium publication in Cell Stem Cell Conference procedings Resaerch seminars
Start Year 2010
 
Description HD iPS Consortium 
Organisation Johns Hopkins University
Country United States 
Sector Academic/University 
PI Contribution Development of HD iPS consortium, HD iPS cell neuronal differentiation and characteristion of disease phenotype. Electrophysiological studies
Collaborator Contribution Cedars Sinai, Svendsen Lab- HDiPS derivation phenotyping Irvive, Thompson Lab- Transcriptomics Johns Hopkins, Ross Lab, Proteomics, neurodegeneration phenotyping Gladstone, Finkbeiner lab-High content neuronal imaging/phenotyping Milan, Cattaneo lab-cell differentiation Harvard, MacDonald Gusella lab-HD genetics, metabolomics
Impact HD iPS consortium publication in Cell Stem Cell Conference procedings Resaerch seminars
Start Year 2010
 
Description HD iPS Consortium 
Organisation University of California, Irvine
Country United States 
Sector Academic/University 
PI Contribution Development of HD iPS consortium, HD iPS cell neuronal differentiation and characteristion of disease phenotype. Electrophysiological studies
Collaborator Contribution Cedars Sinai, Svendsen Lab- HDiPS derivation phenotyping Irvive, Thompson Lab- Transcriptomics Johns Hopkins, Ross Lab, Proteomics, neurodegeneration phenotyping Gladstone, Finkbeiner lab-High content neuronal imaging/phenotyping Milan, Cattaneo lab-cell differentiation Harvard, MacDonald Gusella lab-HD genetics, metabolomics
Impact HD iPS consortium publication in Cell Stem Cell Conference procedings Resaerch seminars
Start Year 2010
 
Description HD iPS Consortium 
Organisation University of California, San Francisco
Department Gladstone Institute of Neurological Disease
Country United States 
Sector Academic/University 
PI Contribution Development of HD iPS consortium, HD iPS cell neuronal differentiation and characteristion of disease phenotype. Electrophysiological studies
Collaborator Contribution Cedars Sinai, Svendsen Lab- HDiPS derivation phenotyping Irvive, Thompson Lab- Transcriptomics Johns Hopkins, Ross Lab, Proteomics, neurodegeneration phenotyping Gladstone, Finkbeiner lab-High content neuronal imaging/phenotyping Milan, Cattaneo lab-cell differentiation Harvard, MacDonald Gusella lab-HD genetics, metabolomics
Impact HD iPS consortium publication in Cell Stem Cell Conference procedings Resaerch seminars
Start Year 2010
 
Description HD iPS Consortium 
Organisation University of Milan
Country Italy 
Sector Academic/University 
PI Contribution Development of HD iPS consortium, HD iPS cell neuronal differentiation and characteristion of disease phenotype. Electrophysiological studies
Collaborator Contribution Cedars Sinai, Svendsen Lab- HDiPS derivation phenotyping Irvive, Thompson Lab- Transcriptomics Johns Hopkins, Ross Lab, Proteomics, neurodegeneration phenotyping Gladstone, Finkbeiner lab-High content neuronal imaging/phenotyping Milan, Cattaneo lab-cell differentiation Harvard, MacDonald Gusella lab-HD genetics, metabolomics
Impact HD iPS consortium publication in Cell Stem Cell Conference procedings Resaerch seminars
Start Year 2010
 
Description Hypoxia and Stem Cell Differentiation 
Organisation Ruskinn Technology Ltd
Country United Kingdom 
Sector Private 
PI Contribution Investigationof hypoxia in the regulation of stem cell neuronal differentiation. Protocol development
Collaborator Contribution Development of controlled environment technology
Impact Research synposium Seminars Company literature
Start Year 2010
 
Description Hypoxic regulation of stem cell neural differentiation 
Organisation Ruskinn Technology Ltd
Country United Kingdom 
Sector Private 
PI Contribution We provide stem cell expertise and experimental data for product development
Collaborator Contribution Use of proprietry and state-of-the -art equipment
Impact KESS PhD studentship Collaboration is multidisciplinarycombining stem cell research and engineering
Start Year 2010
 
Description Medium Spiny Neuron Differentiation consortium 
Organisation University of Barcelona
Country Spain 
Sector Academic/University 
PI Contribution We established a consortium with CHDI funding and project management to understand and establish protocols for medium spiny neuron differentiation. We focus on human ES and iPS protocols, transcription factor and small molecule driven differentiation
Collaborator Contribution University of Milan, Cattaneo Lab-expertise in Huntington's disease, neural stem cell biology and developmental biology University of Barcelona, Canals Lab, Mouse striatal developmental biology and genetics
Impact Research seminars
Start Year 2011
 
Description Medium Spiny Neuron Differentiation consortium 
Organisation University of Milan
Country Italy 
Sector Academic/University 
PI Contribution We established a consortium with CHDI funding and project management to understand and establish protocols for medium spiny neuron differentiation. We focus on human ES and iPS protocols, transcription factor and small molecule driven differentiation
Collaborator Contribution University of Milan, Cattaneo Lab-expertise in Huntington's disease, neural stem cell biology and developmental biology University of Barcelona, Canals Lab, Mouse striatal developmental biology and genetics
Impact Research seminars
Start Year 2011
 
Description Laboratory open days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We hold open days for HD and PD patient and support groups to inform them of ongoing research related to stem cells and brain repair

Education and support for patient groups
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
 
Description Local Community 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Sparked discussion and debate in local community groups on stem cell science, its potential and ethics

Major general interest and requests recieved for further information.
Year(s) Of Engagement Activity 2011,2012