Therapeutic and Research Potential of Human Stem Cells Dr Stephen L Minger Dr Stephen L Minger Director, Stem Cell Biology Laboratory Director, Stem Cell Biology Laboratory Wolfson Centre for Age-Related Diseases Wolfson Centre for Age-Related Diseases King’s College London King’s College London Senior Editor – Regenerative Medicine Senior Editor – Regenerative Medicine Stem Cell Expert – UK Gene Therapy Stem Cell Expert – UK Gene Therapy Advisory Committee (GTAC) Advisory Committee (GTAC)
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Therapeutic and Research Potential of Human Stem Cells Dr Stephen L Minger Director, Stem Cell Biology Laboratory Wolfson Centre for Age-Related Diseases.
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Therapeutic and Research Potential of Human
Stem Cells
Dr Stephen L MingerDr Stephen L MingerDirector, Stem Cell Biology LaboratoryDirector, Stem Cell Biology Laboratory
Wolfson Centre for Age-Related DiseasesWolfson Centre for Age-Related DiseasesKing’s College LondonKing’s College London
Senior Editor – Regenerative MedicineSenior Editor – Regenerative Medicine
Stem Cell Expert – UK Gene Therapy Stem Cell Expert – UK Gene Therapy Advisory Committee (GTAC)Advisory Committee (GTAC)
Parkinson’s Disease and the Parkinson’s Disease and the BrainBrain
Progressive and sustainedimprovement in transplantfunction over ten years inhuman graft recipient
Piccini et al, 1999, NatureNeurosci, 2
Stem Cells – Types, Flavours and Sources
Pluripotent Multipotent
Multipotent
Multipotent
Adult Neurogenesis
Human adult braincontains proliferativeneural stem cells in dentate gyrus and lateral ventricle wall (SVZ) that generate new neurons throughout life
Eriksson et al, 1998, NatureMed, 4, 1313
Regulators of Adult Regulators of Adult NeurogenesisNeurogenesis
Human Embryo Research in Human Embryo Research in UKUK
Human Fertilisation and Embryology Authority Human Fertilisation and Embryology Authority Created in 1990Created in 1990
All Reproductive Medicine & Human Embryo All Reproductive Medicine & Human Embryo Research must be licensed by HFEAResearch must be licensed by HFEA
HFEA-Licensed Embryo Research AreasHFEA-Licensed Embryo Research Areas Treatment of InfertilityTreatment of Infertility Causes of Congenital DiseasesCauses of Congenital Diseases Causes of MiscarriageCauses of Miscarriage Development of more Effective ConceptionDevelopment of more Effective Conception Improvements in Preimplantation Genetic DiagnosisImprovements in Preimplantation Genetic Diagnosis Provide Understanding of Human DevelopmentProvide Understanding of Human Development Provide Understanding of Human DiseaseProvide Understanding of Human Disease Enable Development of Therapies of Human DiseaseEnable Development of Therapies of Human Disease
License for Derivation of Human License for Derivation of Human ES cells from UK Human ES cells from UK Human
Fertilisation and Embryology Fertilisation and Embryology AuthorityAuthority
Awarded to Drs Susan Pickering, Stephen Awarded to Drs Susan Pickering, Stephen Minger & Professor Peter Braude in May 2002 – Minger & Professor Peter Braude in May 2002 – renewed in 2005 for three additional yearsrenewed in 2005 for three additional years
Derivation from donated embryos with informed Derivation from donated embryos with informed consentconsentNo financial inducement for donationNo financial inducement for donationCannot create embryos for stem cell derivationCannot create embryos for stem cell derivationAll cell lines must be deposited in UK Stem Cell Bank All cell lines must be deposited in UK Stem Cell Bank and made and made freely available to other research groupsfreely available to other research groupsCell Nuclear Replacement (Therapeutic) permitted with Cell Nuclear Replacement (Therapeutic) permitted with licenselicenseCell Nuclear Replacement (Reproductive) banned with Cell Nuclear Replacement (Reproductive) banned with criminal criminal penaltiespenalties
Early human development in vitro
Late Day 1 2- cells
Day 1
Day 2 4-cells Day 3 8-cells
Day 4 Morula
Blastocyst Day 5
Hatching Day 6Hatched Late Day 6
ICM
Day 4
ICM
The inner cell mass - contains pluripotent stem cells
With Good Karma, Embryos, andCulture Conditions, Human ESCells Can Be Established At Frequency of ~10%
A, B, Cystic Fibrosis Line (CF-1)C HES Cell Line (WT-4)
Macular Degeneration, Retinitis Pigmentosa (Ali, Institute of Ophthalmology)Macular Degeneration, Retinitis Pigmentosa (Ali, Institute of Ophthalmology) Endocrine DisordersEndocrine Disorders
Type I Diabetes (Jones, Persuad & King’s Islet Transplant Programme)Type I Diabetes (Jones, Persuad & King’s Islet Transplant Programme) Hepatic RegenerationHepatic Regeneration
Hepatic Insufficiency (King’s Liver Transplant Programme)Hepatic Insufficiency (King’s Liver Transplant Programme) Joint and Bone DestructionJoint and Bone Destruction
Cartilage Repair ( De Bari, Dell’Accio)Cartilage Repair ( De Bari, Dell’Accio) Bone Replacement (Grigoriadis)Bone Replacement (Grigoriadis)
Stem Cell BioprocessingStem Cell Bioprocessing Bioengineering/Scale up (Mason, UCL)Bioengineering/Scale up (Mason, UCL)
Developments Required for Therapeutic Developments Required for Therapeutic Application of Human ES Cells To Application of Human ES Cells To Parkinson’s Disease – Preclinical Parkinson’s Disease – Preclinical
Generation of A9-Mesencephalic Dopaminergic Neural Stem Cells Generation of A9-Mesencephalic Dopaminergic Neural Stem Cells by Genetic Engineering – not A10by Genetic Engineering – not A10
Characterisation of Dopaminergic Progenitor CellsCharacterisation of Dopaminergic Progenitor Cells Testing of A9 Stem Cells in Rat PD Models Testing of A9 Stem Cells in Rat PD Models Identification of Cell-Surface Proteins Unique to A9 Dopa Stem Cells Identification of Cell-Surface Proteins Unique to A9 Dopa Stem Cells
by Mass Spectroscopy (if required)by Mass Spectroscopy (if required) Selection of A9 Neural Stem Cells by SortingSelection of A9 Neural Stem Cells by Sorting Long-term Safety and Efficacy Testing of A9 Cells in Rodent -> Long-term Safety and Efficacy Testing of A9 Cells in Rodent ->
Primate Models of PDPrimate Models of PD
Developments Required for Therapeutic Developments Required for Therapeutic Application of Human ES Cells To Application of Human ES Cells To
Delivery of Cells for Therapeutic Applications – Good Delivery of Cells for Therapeutic Applications – Good Experience with Foetal Cell Transplantation, Efficacy Experience with Foetal Cell Transplantation, Efficacy Proportional to Number of DA Neurons Implanted Proportional to Number of DA Neurons Implanted
Need for Standardised Neurosurgical Protocol Need for Standardised Neurosurgical Protocol Requirement for Strict Inclusion/Exclusion Criteria Requirement for Strict Inclusion/Exclusion Criteria
for Patient Selection – Reduce Variability between for Patient Selection – Reduce Variability between PatientsPatients
Generation of Animal-Free, Chemically Defined Generation of Animal-Free, Chemically Defined Culture Conditions -> No XenoproductsCulture Conditions -> No Xenoproducts
Immune Response – Short term (2-3 yrs) minimal Immune Response – Short term (2-3 yrs) minimal immunosuppression supportive/required for graft immunosuppression supportive/required for graft survivalsurvival
Somatic Cell NuclearReplacement
(Cloning)
Can it work in Humans?
Should it be allowed?
How can we use this technology for therapy and/or research?
Strengths of UK Stem Cell Strengths of UK Stem Cell ResearchResearch
World-class academic research centresWorld-class academic research centres Tight regulation on Assisted Reproduction & Tight regulation on Assisted Reproduction &
Human Embryo Research by HFEAHuman Embryo Research by HFEA Government Commitment to Stem Cell Research Government Commitment to Stem Cell Research
(~£45 million – 2003-2004); £350-800 million 10-(~£45 million – 2003-2004); £350-800 million 10-year strategy from Chancellor’s Office announced year strategy from Chancellor’s Office announced Dec 2005 Dec 2005
Government Funded UK Stem Cell Bank for foetal, Government Funded UK Stem Cell Bank for foetal, adult & embryonic human stem cell linesadult & embryonic human stem cell lines
London Regenerative Medicine Network – drive London Regenerative Medicine Network – drive towards clinical applicationstowards clinical applications
UK Stem Cell Network – integration of all UK UK Stem Cell Network – integration of all UK regional networkregional network
Stem Cell Biology LaboratoryWolfson Centre for Age-Related Diseases
Sarah PringleSarah PringleSiobhán ConnorSiobhán Connor Zhenling LuoZhenling LuoKaterina VaranouKaterina VaranouWoojin LeeWoojin Lee
Julie GhoshJulie GhoshDaniel WebberDaniel WebberJessica CookeJessica CookeHannah TaylorHannah Taylor
Medical Research Council, Edmond J Safra Foundation, BBSRC, ESRC, EPSRC, Medical Research Council, Edmond J Safra Foundation, BBSRC, ESRC, EPSRC, European Commission, Oliver Bird Foundation, UK DTI, European Commission, Oliver Bird Foundation, UK DTI, Francesca Patrizi,Francesca Patrizi,
High Q Foundation, Wellcome Trust, Huntington’s Disease SocietyHigh Q Foundation, Wellcome Trust, Huntington’s Disease Society, John &, John & Helen Helen Robertson, Alzheimer’s Research Trust, Liz & John Hancock, Guy’s & St Thomas’ Robertson, Alzheimer’s Research Trust, Liz & John Hancock, Guy’s & St Thomas’
Charitable TrustCharitable Trust
Adult NeurogenesisAdult NeurogenesisClive BallardClive BallardOmar PathmanabanOmar PathmanabanChirstos ToliasChirstos ToliasElaine Perry (Newcastle)Elaine Perry (Newcastle)Robert Perry (Newcastle)Robert Perry (Newcastle)Aaron Cheung (GSK)Aaron Cheung (GSK)