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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Simon Melov

PROVIDER: E-GEOD-37547 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

Analysis of differentially expressed genes between Huntington’s disease and control iPSCs derived GABA MS-like neurons

Project description:Huntington’s disease (HD) is an incurable hereditary neurodegenerative disorder, which manifests itself as a loss of GABAergic medium spiny (GABA MS) neurons in the striatum and caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. There is no cure for HD, existing pharmaceutical can only relieve its symptoms. Here, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were then efficiently differentiated into GABA MS-like neurons under defined culture conditions. Analysis of differentially expressed genes between Huntington’s disease and wild type iPSCs derived GABA MS-like neurons has been performed.

2016-02-04 | GSE77558 | GEO

Transcriptome profiling in knock-in mouse models of Huntington's disease [Striatum_miRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the striatum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2016-02-15 | E-GEOD-65773 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Liver_mRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the liver of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2016-02-15 | E-GEOD-65772 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Liver_miRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the liver of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2016-02-15 | E-GEOD-65771 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Striatum_mRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the striatum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2016-02-15 | E-GEOD-65774 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Hippocampus_mRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the hippocampus of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2015-11-03 | E-GEOD-73503 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Cerebellum_miRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals. miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the cerebellum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2015-11-03 | E-GEOD-73505 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Hippocampus_miRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals. miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the hippocampus of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2015-11-03 | E-GEOD-73507 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [cerebellum_mRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the cerebellum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2015-11-03 | E-GEOD-73468 | biostudies-arrayexpress

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