A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells

Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients' fibroblasts into induced pluripotent stem cells (iPSC) and di...

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Published in	Molecular and cellular neuroscience Vol. 56; pp. 355 - 364
Main Authors	Burkhardt, Matthew F., Martinez, Fernando J., Wright, Sarah, Ramos, Carla, Volfson, Dmitri, Mason, Michael, Garnes, Jeff, Dang, Vu, Lievers, Jeffery, Shoukat-Mumtaz, Uzma, Martinez, Rita, Gai, Hui, Blake, Robert, Vaisberg, Eugeni, Grskovic, Marica, Johnson, Charles, Irion, Stefan, Bright, Jessica, Cooper, Bonnie, Nguyen, Leane, Griswold-Prenner, Irene, Javaherian, Ashkan
Format	Journal Article
Language	English
Published	United States Elsevier Inc 01.09.2013
Subjects	ALS Amyotrophic Lateral Sclerosis - metabolism Amyotrophic Lateral Sclerosis - pathology Case-Control Studies Cell Differentiation Cellular Reprogramming Digoxin DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug screening Fibroblasts - cytology Fibroblasts - metabolism Fibroblasts - pathology Humans Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology iPS Motor Neurons - cytology Motor Neurons - metabolism Motor Neurons - pathology TDP-43 iPSC-CN Digoxin iPSC-MN TDP-43 HTS iPSC FTLD ALS Drug screening iPS SOD1 fronto-temporal lobar degeneration high-throughput screening amyotrophic lateral sclerosis TARDBP, TAR DNA binding protein induced pluripotent stem cell-derived motor neurons induced pluripotent stem cells induced pluripotent stem cell-derived cortical neurons superoxide dismutase 1
Online Access	Get full text
ISSN	1044-7431 1095-9327 1095-9327
DOI	10.1016/j.mcn.2013.07.007

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Abstract	Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients' fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modeling for drug screening.
AbstractList	Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients' fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modeling for drug screening. Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients’ fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modelling for drug screening. Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients' fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modeling for drug screening.Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients' fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modeling for drug screening.
Author	Vaisberg, Eugeni Ramos, Carla Gai, Hui Blake, Robert Shoukat-Mumtaz, Uzma Grskovic, Marica Martinez, Rita Dang, Vu Burkhardt, Matthew F. Martinez, Fernando J. Bright, Jessica Nguyen, Leane Wright, Sarah Mason, Michael Johnson, Charles Griswold-Prenner, Irene Garnes, Jeff Irion, Stefan Cooper, Bonnie Javaherian, Ashkan Volfson, Dmitri Lievers, Jeffery
AuthorAffiliation	1 iPierian Inc., 951 Gateway Blvd, South San Francisco, CA 94080
AuthorAffiliation_xml	– name: 1 iPierian Inc., 951 Gateway Blvd, South San Francisco, CA 94080
Author_xml	– sequence: 1 givenname: Matthew F. surname: Burkhardt fullname: Burkhardt, Matthew F. – sequence: 2 givenname: Fernando J. surname: Martinez fullname: Martinez, Fernando J. – sequence: 3 givenname: Sarah surname: Wright fullname: Wright, Sarah – sequence: 4 givenname: Carla surname: Ramos fullname: Ramos, Carla – sequence: 5 givenname: Dmitri surname: Volfson fullname: Volfson, Dmitri – sequence: 6 givenname: Michael surname: Mason fullname: Mason, Michael – sequence: 7 givenname: Jeff surname: Garnes fullname: Garnes, Jeff – sequence: 8 givenname: Vu surname: Dang fullname: Dang, Vu – sequence: 9 givenname: Jeffery surname: Lievers fullname: Lievers, Jeffery – sequence: 10 givenname: Uzma surname: Shoukat-Mumtaz fullname: Shoukat-Mumtaz, Uzma – sequence: 11 givenname: Rita surname: Martinez fullname: Martinez, Rita – sequence: 12 givenname: Hui surname: Gai fullname: Gai, Hui – sequence: 13 givenname: Robert surname: Blake fullname: Blake, Robert – sequence: 14 givenname: Eugeni surname: Vaisberg fullname: Vaisberg, Eugeni – sequence: 15 givenname: Marica surname: Grskovic fullname: Grskovic, Marica – sequence: 16 givenname: Charles surname: Johnson fullname: Johnson, Charles – sequence: 17 givenname: Stefan surname: Irion fullname: Irion, Stefan – sequence: 18 givenname: Jessica surname: Bright fullname: Bright, Jessica – sequence: 19 givenname: Bonnie surname: Cooper fullname: Cooper, Bonnie – sequence: 20 givenname: Leane surname: Nguyen fullname: Nguyen, Leane – sequence: 21 givenname: Irene surname: Griswold-Prenner fullname: Griswold-Prenner, Irene email: Irene.Griswold-Prenner@ipierian.com – sequence: 22 givenname: Ashkan surname: Javaherian fullname: Javaherian, Ashkan email: ashkanjavaherian@gmail.com
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Keywords	iPSC-CN Digoxin iPSC-MN TDP-43 HTS iPSC FTLD ALS Drug screening iPS SOD1 fronto-temporal lobar degeneration high-throughput screening amyotrophic lateral sclerosis TARDBP, TAR DNA binding protein induced pluripotent stem cell-derived motor neurons induced pluripotent stem cells induced pluripotent stem cell-derived cortical neurons superoxide dismutase 1
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work Present address: The J. David Gladstone Institutes, 1650 Owens Street, San Francisco California 94158.
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Snippet	Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered...
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SubjectTerms	ALS Amyotrophic Lateral Sclerosis - metabolism Amyotrophic Lateral Sclerosis - pathology Case-Control Studies Cell Differentiation Cellular Reprogramming Digoxin DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug screening Fibroblasts - cytology Fibroblasts - metabolism Fibroblasts - pathology Humans Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology iPS Motor Neurons - cytology Motor Neurons - metabolism Motor Neurons - pathology TDP-43
Title	A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells
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