Induced Stem Cells in Research and Therapy of Neuropsychiatric Disorders

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1 Berlin-Brandenburg Center for Regenerative Therapies Induced Stem Cells in Research and Therapy of Neuropsychiatric Disorders Josef Priller Department of Neuropsychiatry Laboratory of Molecular Psychiatry Charité-Universitätsmedizin Berlin

2 Induced pluripotent stem cells (ipscs) Inner cell mass Blastozyste ES cells Neural induction Direct differentiation Fetal brain Neural cells Genetic modification Adult bone marrow ipscs Differentiated tissues (e.g. skin, adipose tissue, blood) Neural induction Direct differentiation Hematopoietic cells Mesenchymal stromal cells Endothelial progenitor cells Adult neural stem cells Selection Enrichment modified from Tai & Svendsen, Curr Opinion Pharmacol 2004

3 Induced pluripotent stem cells (ipscs) adult human dermal fibroblasts (HDFs): Slc7a1 (retrovirus) hu Oct3/4, Sox2, Klf4, c-myc (retrovirus) Takahashi et al., Cell 2007

4 Induced pluripotent stem cells (ipscs) ßTub TH Takahashi et al., Cell 2007

5 Formation of teratomas by hes cells Cartilage (mesoderm) GI epithelium (endoderm) Muscle (mesoderm) Lung epithelium (endoderm) Epithelium (ectoderm) s.c. injection of hes cells (H9 line) into immunodeficient mice Lensch et al., Cell Stem Cell 2007

6 Formation of teratomas by ipscs s.c. injection of ipscs into immunodeficient mice Takahashi et al., Cell 2007

7 Cell transplantation

8 Ectopic transplantation of fetal cells in PD Transplantation Increased activity (arrow) on 18 F- Dopa PET after transplantation of human fetal neurons (red cross) Björklund et al., Lancet Neurol 2003

9 Issues with fetal grafts in neurodegenerative diseases Human fetal tissue Logistics - Limited availability - No amplification in vitro - No banking Quality control - No standardization - Risk of infections - Dissection accuracy variable Regulatory + Organ transplantation Immunogenicity + Allografts, but long-term survival Safety - Cyst formation - Overgrowth Efficacy + modified from Nicoleau et al., Neurotherapeutics 2011

10 Issues with pluripotent stem cells Human pluripotent stem cells Logistics + In vitro amplification and production + Banking possible - Differentiation protocols incomplete Quality control + Standardization + GMP-grade hes cells available - No GMP-grade hipscs available Regulatory - Drug Immunogenicity + Patient-derived or haplotyped - Teratomas are immunogenic Safety - Tumor/teratoma formation - Overgrowth - Genetic and epigenetic instability Efficacy? modified from Nicoleau et al., Neurotherapeutics 2011

11 Cell differentiation for transplantation in HD Nicoleau et al., Neurotherapeutics 2011

12 Mechanisms of disease and drug development

13 Schizophrenia Prevalence 1% Decreased brain volume, aberrant neurotransmitter signalling, reduced dendritic arborization, impaired myelination Complex genetic disorder Neurodevelopmental hypothesis

14 Schizophrenia-iPSCs Brennand et al. Nature 2011 Brennand & Gage, Stem Cells 2011

15 Rett syndrome Prevalence 1/10,000 live female births Decreased brain volume, smaller neuronal cell bodies and reduced numbers of synapses Mutations in MECP2 Neurodevelopmental disorder

16 Rett-iPSCs Marchetto et al., Cell 2010

17 Rett-iPSCs: response to IGF-1 treatment Marchetto et al., Cell 2010

18 Potential and limitations of hipscs Human brain disease in a dish BUT: High variablity (neuron-to-neuron, hipsc-to-hipsc and patient-to-patient) Still expensive and time-consuming technique Difficult validation

19 Complementary approaches to brain diseases Dolmetsch & Geschwind, Cell 2011

20 Speakers Phil Horner, Center on Human Development and Disability Seattle, University of Washington, USA Neural stem cells derived from human ips improve forelimb recovery following spinal cord injury Philip H. Schwartz, National Human Neural Stem Cell Resource & Autism ipsc Biorepository, Children's Hospital of Orange County Research Institute, USA An approach to immune-matched neurotherapy in pediatric neurodegenerative disease