title: A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells.
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.
authors.affiliation: iPierian Inc., 951 Gateway Blvd, South San Francisco, CA 94080, United States.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Burkhardt
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: Sarah
authors.initials: S
authors.lastname: Wright
authors.forename: Carla
authors.initials: C
authors.lastname: Ramos
authors.forename: Dmitri
authors.initials: D
authors.lastname: Volfson
authors.forename: Michael
authors.initials: M
authors.lastname: Mason
authors.forename: Jeff
authors.initials: J
authors.lastname: Garnes
authors.forename: Vu
authors.initials: V
authors.lastname: Dang
authors.forename: Jeffery
authors.initials: J
authors.lastname: Lievers
authors.forename: Uzma
authors.initials: U
authors.lastname: Shoukat-Mumtaz
authors.forename: Rita
authors.initials: R
authors.lastname: Martinez
authors.forename: Hui
authors.initials: H
authors.lastname: Gai
authors.forename: Robert
authors.initials: R
authors.lastname: Blake
authors.forename: Eugeni
authors.initials: E
authors.lastname: Vaisberg
authors.forename: Marica
authors.initials: M
authors.lastname: Grskovic
authors.forename: Charles
authors.initials: C
authors.lastname: Johnson
authors.forename: Stefan
authors.initials: S
authors.lastname: Irion
authors.forename: Jessica
authors.initials: J
authors.lastname: Bright
authors.forename: Bonnie
authors.initials: B
authors.lastname: Cooper
authors.forename: Leane
authors.initials: L
authors.lastname: Nguyen
authors.forename: Irene
authors.initials: I
authors.lastname: Griswold-Prenner
authors.forename: Ashkan
authors.initials: A
authors.lastname: Javaherian
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins
keywords: ALS; Digoxin; Drug screening; FTLD; HTS; SOD1; TARDBP, TAR DNA binding protein; TDP-43; amyotrophic lateral sclerosis; fronto-temporal lobar degeneration; high-throughput screening; iPS; iPSC; iPSC-CN; iPSC-MN; induced pluripotent stem cell-derived cortical neurons; induced pluripotent stem cell-derived motor neurons; induced pluripotent stem cells; superoxide dismutase 1
references.citation: Brain Res. 2007 Dec 12;1184:284-94
references.pmid: 17963732
references.citation: Curr Biol. 2004 Mar 23;14(6):488-92
references.pmid: 15043813
references.citation: Biochem Biophys Res Commun. 2006 Dec 22;351(3):602-11
references.pmid: 17084815
references.citation: Science. 2008 Aug 29;321(5893):1218-21
references.pmid: 18669821
references.citation: Nat Genet. 2008 May;40(5):572-4
references.pmid: 18372902
references.citation: Am J Pathol. 2007 Jul;171(1):227-40
references.pmid: 17591968
references.citation: Neurology. 2010 Dec 14;75(24):2204-11
references.pmid: 21172843
references.citation: Neuropathology. 2010 Apr;30(2):170-81
references.pmid: 20102522
references.citation: Ann Neurol. 2007 May;61(5):435-45
references.pmid: 17469117
references.citation: Nat Rev Neurosci. 2006 Sep;7(9):710-23
references.pmid: 16924260
references.citation: Acta Neuropathol. 2007 Sep;114(3):221-9
references.pmid: 17653732
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5803-8
references.pmid: 22451909
references.citation: Acta Neuropathol. 2012 Nov;124(5):717-32
references.pmid: 22993125
references.citation: FEBS Lett. 2008 Aug 20;582(19):2899-904
references.pmid: 18656473
references.citation: Nat Biotechnol. 2009 Mar;27(3):275-80
references.pmid: 19252484
references.citation: J Neurosci. 2010 Jan 13;30(2):639-49
references.pmid: 20071528
references.citation: Amyotroph Lateral Scler. 2010 May 3;11(3):321-7
references.pmid: 20225928
references.citation: Hum Mol Genet. 2004 Feb 15;13(4):437-46
references.pmid: 14709594
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Arch Neurol. 2007 Oct;64(10):1388-94
references.pmid: 17923623
references.citation: Science. 2008 Mar 21;319(5870):1668-72
references.pmid: 18309045
references.citation: Neuron. 2005 Jan 20;45(2):207-21
references.pmid: 15664173
references.citation: Cell Stem Cell. 2013 Jun 6;12(6):713-26
references.pmid: 23602540
references.citation: Nat Rev Drug Discov. 2008 Nov;7(11):926-35
references.pmid: 18948999
references.citation: J Biol Chem. 2010 Feb 26;285(9):6826-34
references.pmid: 20040602
references.citation: Lancet Neurol. 2008 May;7(5):409-16
references.pmid: 18396105
references.citation: Ann Neurol. 2007 May;61(5):427-34
references.pmid: 17469116
references.citation: Science. 2006 Oct 6;314(5796):130-3
references.pmid: 17023659
references.citation: J Mol Neurosci. 2011 Nov;45(3):656-62
references.pmid: 21971978
references.citation: Neuropathology. 2009 Dec;29(6):672-83
references.pmid: 19496940
references.citation: Acta Neuropathol. 2009 Feb;117(2):137-49
references.pmid: 19125255
references.citation: Sci Transl Med. 2012 Aug 1;4(145):145ra104
references.pmid: 22855461