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CNV analysis for Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations

ABSTRACT: Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease in disease relevant cells, as well as a promising source for cell replacement therapies for degenerative diseases. However one of the crucial limitations before realizing the full promise of this “disease in a dish” approach has been the inability to do controlled experiments under genetically defined conditions. This is particularly relevant for disorders with long latency periods, such as Parkinson’s disease (PD), where in vitro phenotypes of patient-derived iPSCs are predicted to be subtle and susceptible to significant epistatic effects of genetic background variations. By combining zinc-finger nuclease (ZFN)-mediated genome editing and iPSC technology we provide a generally applicable solution to this key problem by generating isogenic pairs of disease and control human embryonic stem cells (hESCs) and hiPSCs lines that differ exclusively at a susceptibility variant for PD by modifying a single point mutation (A53T) in the α-synuclein gene. The robust capability to genetically correct disease causing point mutations in patient-derived hiPSCs represents not only a significant progress for basic biomedical research but also a major advancement towards hiPSC-based cell replacement therapies using autologous cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE29772 | GEO | 2011/07/26

SECONDARY ACCESSION(S): PRJNA153879

REPOSITORIES: GEO

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Gene Expression Data for Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations

Project description:Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease in disease relevant cells, as well as a promising source for cell replacement therapies for degenerative diseases. However one of the crucial limitations before realizing the full promise of this “disease in a dish” approach has been the inability to do controlled experiments under genetically defined conditions. This is particularly relevant for disorders with long latency periods, such as Parkinson’s disease (PD), where in vitro phenotypes of patient-derived iPSCs are predicted to be subtle and susceptible to significant epistatic effects of genetic background variations. By combining zinc-finger nuclease (ZFN)-mediated genome editing and iPSC technology we provide a generally applicable solution to this key problem by generating isogenic pairs of disease and control human embryonic stem cells (hESCs) and hiPSCs lines that differ exclusively at a susceptibility variant for PD by modifying a single point mutation (A53T) in the α-synuclein gene. The robust capability to genetically correct disease causing point mutations in patient-derived hiPSCs represents not only a significant progress for basic biomedical research but also a major advancement towards hiPSC-based cell replacement therapies using autologous cells. ZFN-mediated genome edited human iPS cells or ES cells were assayed for gene expression

2011-07-25 | E-GEOD-29773 | biostudies-arrayexpress

CNV analysis for Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations

Project description:Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease in disease relevant cells, as well as a promising source for cell replacement therapies for degenerative diseases. However one of the crucial limitations before realizing the full promise of this “disease in a dish” approach has been the inability to do controlled experiments under genetically defined conditions. This is particularly relevant for disorders with long latency periods, such as Parkinson’s disease (PD), where in vitro phenotypes of patient-derived iPSCs are predicted to be subtle and susceptible to significant epistatic effects of genetic background variations. By combining zinc-finger nuclease (ZFN)-mediated genome editing and iPSC technology we provide a generally applicable solution to this key problem by generating isogenic pairs of disease and control human embryonic stem cells (hESCs) and hiPSCs lines that differ exclusively at a susceptibility variant for PD by modifying a single point mutation (A53T) in the ?-synuclein gene. The robust capability to genetically correct disease causing point mutations in patient-derived hiPSCs represents not only a significant progress for basic biomedical research but also a major advancement towards hiPSC-based cell replacement therapies using autologous cells. ZFN-mediated genome edited human iPS cells or ES cells were assayed for genomic variation

2011-07-25 | E-GEOD-29772 | biostudies-arrayexpress

Gene Expression Data for Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations

2011-07-26 | GSE29773 | GEO

Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors

Project description:Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients by viral vector-mediated factor transduction represent a powerful tool for biomedical research and may provide a source for cell replacement therapies. However, the proviruses encoding the reprogramming factors represent a major limitation of the current technology because even low vector expression may alter the differentiation potential of the iPSCs and induce malignant transformation. Here we show that fibroblasts from five patients with idiopathic Parkinson’s disease (PD) can be efficiently reprogrammed into hiPSCs and subsequently differentiated into dopaminergic neurons. Moreover, we derived PD specific hiPSCs free of reprogramming factors using Cre-recombinase excisable viruses. Upon factor deletion these cells maintain a pluripotent state and intact karyotype. Importantly, these factor-free hiPSCs show a global gene expression profile, which is more closely related to hESCs than to hiPSCs carrying the transgenes. Our results indicate that residual transgene expression in conventional virus-carrying hiPSCs can affect their molecular characteristics and that factor-free hiPSCs therefore represent a more suitable source of cells for modeling of human disease.

2009-03-06 | GSE14711 | GEO

aHDF- and PB-iPSC clones from the same individuals

Project description:Hepatocytes generated from human induced pluripotent stem cells (hiPSCs) are unprecedented resources for pharmaceuticals and cell therapy. However, little attention has so far been paid to variations among hiPSC lines in terms of their hepatic differentiation. We developed an improved hepatic differentiation protocol and compared multiple hiPSC lines. This comparison indicated that the hepatic differentiation propensity varies among sibling hiPSC clones derived from the same adult human dermal fibroblasts (aHDFs). In addition, hiPSC clones derived from peripheral blood cells (PB-iPSCs) consistently showed good hepatic differentiation efficiency, whereas many hiPSC clones from adult dermal fibroblasts (aHDF-iPSCs) showed poor hepatic differentiation. However, when we compared hiPSCs from blood and dermal fibroblasts from the same individuals, we found that variations in hepatic differentiation were largely attributable to donor differences, rather than to the types of the original cells. In order to understand the molecular mechanisms underlying the observed variations in hepatic differentiation, we performed microarray analyses of sibling aHDF-iPSC clones, and aHDF- and PB-iPSC clones from the same individuals. Undifferentiated aHDF- and PB-iPSCs from the same individuals (two Parkinson’s disease patients (PD #1 and PD #2) and one adult healthy donor (donor91))

2012-07-15 | E-GEOD-38153 | biostudies-arrayexpress

GENETIC CORRECTION OF HUNTINGTON'S DISEASE PHENOTYPES IN INDUCED PLURIPOTENT STEM CELLS

Project description:Huntington's Disease (HD) is caused by a CAG expansion in the huntingtin gene. Expansion of the polyglutamine tract in the huntingtin protein results in massive cell death in the striatum of HD patients. We report that human induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts can be corrected by replacing the expanded CAG repeat with a normal repeat using homologous recombination, and that the correction persists in iPSC differentiation into DARPP-32 positive neurons in vitro and vivo. Further, correction of the HD-iPSCs normalized pathogenic HD signaling pathways (cadherin, TGF-?, BNDF, caspase activation), and reversed disease phenotypes such as susceptibility to cell death and altered mitochondrial bioenergetics in neural stem cells. The ability to make patient-specific, genetically corrected iPSCs from HD patients will provide relevant disease models in identical genetic backgrounds and is a critical step for the eventual use of these cells in cell replacement therapy. 16 experimental samples were used overall. There were 8 replicates per group, with one group being the control, and the other being the experimental. Comparison was carried out on the Nimblegen platform.

2012-06-14 | E-GEOD-37547 | biostudies-arrayexpress

GBA1 regulates the CLEAR network through Calcineurin and TFEB in cellular models of Parkinson´s disease

Project description:The GBA1 gene encodes the lysosomal enzyme acid-β-glucocerebrosidase (GCase). GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD) and are a genetic risk factor for Parkinson´s disease (PD). Many GBA1 mutations cause aberrant GCase folding and processing but how these impinge on PD pathogenesis remains unclear. We addressed GCase functions in human dopaminergic (DA) neurons derived from engineered GBA1-deficient (GBA1-/-) embryonic stem cells (hESCs) and GBA1N370S PD patient-derived induced pluripotent cells (hiPSCs). GBA1-mutant DA neurons displayed aberrant morphologies and gene expression that were rescued by recombinant GCase treatment. GBA1-/- neurons have hyperactive Calcineurin (CaN) and nuclear localization of the Transcription Factor EB (TFEB). Expression of TFEB targets and lysosomal CLEAR network components were increased in GBA1-/- DA neurons and rescued by GCase replacement and CaN inhibition. Our findings reveal a link between increased CaN activity and loss of GCase, providing a mechanism for the disturbed lysosomal/autophagy pathways in GBA1-associated PD.

2022-12-31 | GSE118511 | GEO

GENETIC CORRECTION OF HUNTINGTON'S DISEASE PHENOTYPES IN INDUCED PLURIPOTENT STEM CELLS

Project description:Huntington's Disease (HD) is caused by a CAG expansion in the huntingtin gene. Expansion of the polyglutamine tract in the huntingtin protein results in massive cell death in the striatum of HD patients. We report that human induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts can be corrected by replacing the expanded CAG repeat with a normal repeat using homologous recombination, and that the correction persists in iPSC differentiation into DARPP-32 positive neurons in vitro and vivo. Further, correction of the HD-iPSCs normalized pathogenic HD signaling pathways (cadherin, TGF-β, BNDF, caspase activation), and reversed disease phenotypes such as susceptibility to cell death and altered mitochondrial bioenergetics in neural stem cells. The ability to make patient-specific, genetically corrected iPSCs from HD patients will provide relevant disease models in identical genetic backgrounds and is a critical step for the eventual use of these cells in cell replacement therapy.

2012-06-15 | GSE37547 | GEO

SNP data from genomic DNA from a subject, fibroblasts, iPSCs and neurons with four copies of SNCA, and genomic DNA from an unaffected first degree relative and equivalent cell lines

Project description:A major barrier to research on Parkinson’s disease (PD) is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells (iPSCs) from patients with PD and differentiate them into neurons affected by disease. We created an iPSC model of PD caused by triplication of SNCA encoding ?-synuclein. ?-Synuclein dysfunction is common to all forms of PD, and SNCA triplication leads to fully penetrant familial PD with accelerated pathogenesis. After differentiation of iPSCs into neurons enriched for midbrain dopaminergic subtypes, those from the patient contain double ?-synuclein protein compared to those from an unaffected relative, precisely recapitulating the cause of PD in these individuals. A measurable biomarker makes this model ideal for drug screening for compounds that reduce levels of ?-synuclein, and for mechanistic experiments to study PD pathogenesis. This SNP microarray study was carried out to confirm presence of SNCA triplication in the affected subject and the derived cell lines. 11 samples were analysed: genomic DNA from the two subjects in the study, the two parent fibroblast lines (AST denoting alpha-synuclein triplication and NAS denoting normal alpha-synuclein), two iPSC lines from each parent fibroblast line (four in total), a human embryonic stem cell line (SHEF4) and two neuronal samples one each from AST and NAS iPSCs).

2011-09-14 | E-GEOD-28366 | biostudies-arrayexpress

DNA methylation analysis in idiopathic and LRRK2-associated Parkinson's disease (PD)

Project description:We performed a genome-wide DNA methylation study in induced pluripotent stem cells (IPSC)-derived dopaminergic neurons (DAn) generated from keratinocytes of monogenic and sporadic Parkinson disease (PD) patients as well as of healthy subjects. We observed extensive DNA methylation changes in DAn from PD patients. These changes were neither present in the original keratinocytes nor in the undifferentiated IPSCs, suggesting latent molecular defects in PD keratinocytes that are manifested only upon differentiation into DAn. We also found that enhancers showing abnormal DNA hypermethylation in PD were enriched for binding sites of transcription factors such as FOXA1, NR3C1, HNF4A and FOSL2 which are involved in the survival of DAn and showed reduced expression. These data suggest that aberrant epigenomic remodeling of IPSC-derived DAn in PD is mediated by the down-regulation of key transcription factors. Our study suggests that future cell replacement strategies should pay careful attention to the correct epigenomic status of the reprogrammed cells, especially when using patient own skin cells.

2015-12-01 | GSE51921 | GEO

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