title: Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models.
abstract: Compelling clinical, social, and economic reasons exist to innovate in the process of drug discovery for neuropsychiatric disorders. The use of patient-specific, induced pluripotent stem cells (iPSCs) now affords the ability to generate neuronal cell-based models that recapitulate key aspects of human disease. In the context of neuropsychiatric disorders, where access to physiologically active and relevant cell types of the central nervous system for research is extremely limiting, iPSC-derived in vitro culture of human neurons and glial cells is transformative. Potential applications relevant to early stage drug discovery, include support of quantitative biochemistry, functional genomics, proteomics, and perhaps most notably, high-throughput and high-content chemical screening. While many phenotypes in human iPSC-derived culture systems may prove adaptable to screening formats, addressing the question of which in vitro phenotypes are ultimately relevant to disease pathophysiology and therefore more likely to yield effective pharmacological agents that are disease-modifying treatments requires careful consideration. Here, we review recent examples of studies of neuropsychiatric disorders using human stem cell models where cellular phenotypes linked to disease and functional assays have been reported. We also highlight technical advances using genome-editing technologies in iPSCs to support drug discovery efforts, including the interpretation of the functional significance of rare genetic variants of unknown significance and for the purpose of creating cell type- and pathway-selective functional reporter assays. Additionally, we evaluate the potential of in vitro stem cell models to investigate early events of disease pathogenesis, in an effort to understand the underlying molecular mechanism, including the basis of selective cell-type vulnerability, and the potential to create new cell-based diagnostics to aid in the classification of patients and subsequent selection for clinical trials. A number of key challenges remain, including the scaling of iPSC models to larger cohorts and integration with rich clinicopathological information and translation of phenotypes. Still, the overall use of iPSC-based human cell models with functional cellular and biochemical assays holds promise for supporting the discovery of next-generation neuropharmacological agents for the treatment and ultimately prevention of a range of severe mental illnesses.
authors.affiliation: Chemical Neurobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Center for Experimental Drugs & Diagnostics, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States. Electronic address: shaggarty@mgh.harvard.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.affiliation: Chemical Neurobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Center for Experimental Drugs & Diagnostics, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States.
authors.forename: M Catarina
authors.initials: MC
authors.lastname: Silva
authors.affiliation: AstraZeneca Neuroscience iMED, 141 Portland Street, Cambridge, MA 02139, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Cross
authors.affiliation: AstraZeneca Neuroscience iMED, 141 Portland Street, Cambridge, MA 02139, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Center for Experimental Drugs & Diagnostics, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States.
authors.forename: Roy H
authors.initials: RH
authors.lastname: Perlis
mesh_terms: D018929:Cell Culture Techniques / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D001523:Mental Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D057285:Precision Medicine / Q000379:methods*
keywords: Autism spectrum disorders; Bipolar disorder; CRISPR-Cas9; Dementia; Drug discovery; High-content imaging; High-throughput screening; Human stem cells; Neuropharmacology; Schizophrenia; iPSC models
references.citation: Mol Neurodegener. 2015 Sep 15;10:46
references.pmid: 26373282
references.citation: Eur J Hum Genet. 2016 Jun;24(6):871-80
references.pmid: 26443267
references.citation: J Neurosci. 2015 Oct 21;35(42):14234-50
references.pmid: 26490863
references.citation: Nature. 2012 Jan 25;482(7384):216-20
references.pmid: 22278060
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):2029-34
references.pmid: 19208815
references.citation: Biol Psychiatry. 2014 Jun 15;75(12):952-60
references.pmid: 23876186
references.citation: Curr Pharm Des. 2015;21(31):4556-65
references.pmid: 26486142
references.citation: Brain Res. 2016 May 1;1638(Pt A):57-73
references.pmid: 26254731
references.citation: Am J Med Genet. 1991 Dec 1;41(3):289-94
references.pmid: 1724112
references.citation: Hum Mol Genet. 2012 Feb 1;21(3):681-91
references.pmid: 22048960
references.citation: J Neurodev Disord. 2011 Jun;3(2):162-74
references.pmid: 21533542
references.citation: Nat Biotechnol. 2011 Jul 07;29(8):731-4
references.pmid: 21738127
references.citation: Cell Rep. 2014 Nov 20;9(4):1173-82
references.pmid: 25456120
references.citation: Stem Cells Dev. 2014 Aug 1;23(15):1777-87
references.pmid: 24654675
references.citation: Annu Rev Pathol. 2012;7:219-45
references.pmid: 22017584
references.citation: Neuron. 2015 Apr 8;86(1):160-74
references.pmid: 25856492
references.citation: PLoS One. 2015 Jul 14;10(7):e0132387
references.pmid: 26173148
references.citation: Hippocampus. 2012 Jun;22(6):1220-4
references.pmid: 22128095
references.citation: Nature. 2014 Jul 24;511(7510):421-7
references.pmid: 25056061
references.citation: Cell Rep. 2014 Apr 10;7(1):1-11
references.pmid: 24703839
references.citation: Front Genet. 2015 Jun 03;6:192
references.pmid: 26089834
references.citation: Front Psychiatry. 2012 Mar 23;3:24
references.pmid: 22470355
references.citation: Nat Med. 2015 Sep;21(9):979-88
references.pmid: 26340119
references.citation: Stem Cell Reports. 2013 Aug 29;1(3):226-34
references.pmid: 24319659
references.citation: Curr Pharm Des. 2010;16(5):488-501
references.pmid: 19909227
references.citation: Nat Neurosci. 2013 Feb;16(2):201-9
references.pmid: 23313911
references.citation: Mol Psychiatry. 2013 Dec;18(12):1302-7
references.pmid: 23070075
references.citation: Mol Psychiatry. 2011 Nov;16(11):1076-87
references.pmid: 21709685
references.citation: Hum Mol Genet. 2011 Jun 1;20(11):2103-15
references.pmid: 21372149
references.citation: Mol Psychiatry. 2015 Mar;20(3):361-8
references.pmid: 24686136
references.citation: Brain. 2015 Nov;138(Pt 11):3345-59
references.pmid: 26220942
references.citation: Cell Stem Cell. 2013 Apr 4;12(4):487-96
references.pmid: 23434393
references.citation: Biol Psychiatry. 2014 Apr 1;75(7):565-73
references.pmid: 24629669
references.citation: PLoS One. 2013 May 29;8(5):e65324
references.pmid: 23734247
references.citation: ACS Chem Biol. 2014 Aug 15;9(8):1736-46
references.pmid: 24877719
references.citation: Mol Biol Cell. 2012 Apr;23(8):1435-45
references.pmid: 22357617
references.citation: PLoS Med. 2005 Aug;2(8):e124
references.pmid: 16060722
references.citation: Am J Hum Genet. 2004 Dec;75(6):1149-54
references.pmid: 15499549
references.citation: Cell. 2015 May 21;161(5):1202-14
references.pmid: 26000488
references.citation: Neuroscience. 2014 Apr 4;264:112-30
references.pmid: 23376737
references.citation: Neuron. 2011 Sep 22;71(6):1030-42
references.pmid: 21943601
references.citation: Nat Rev Genet. 2010 Sep;11(9):636-46
references.pmid: 20717154
references.citation: ACS Chem Neurosci. 2010 Jan 28;1(4):325-342
references.pmid: 20495671
references.citation: Neuron. 2015 Jul 1;87(1):28-46
references.pmid: 26139368
references.citation: Curr Opin Neurobiol. 2015 Feb;30:131-8
references.pmid: 25544106
references.citation: PLoS One. 2015 Nov 10;10(11):e0142693
references.pmid: 26554713
references.citation: Sci Rep. 2015 Mar 17;5:9205
references.pmid: 25777362
references.citation: Mol Psychiatry. 2011 Apr;16(4):358-60
references.pmid: 21339753
references.citation: Cell Signal. 2016 Jul;28(7):749-52
references.pmid: 26432168
references.citation: Nature. 2014 Feb 13;506(7487):179-84
references.pmid: 24463507
references.citation: Sci Transl Med. 2011 Jan 5;3(64):64ra1
references.pmid: 21209411
references.citation: Stem Cell Reports. 2015 Jul 14;5(1):83-96
references.pmid: 26143746
references.citation: Mol Psychiatry. 2004 Jul;9(7):684-97, 643
references.pmid: 15098003
references.citation: PLoS One. 2011;6(10):e26203
references.pmid: 22022567
references.citation: Mol Psychiatry. 2012 Dec;17(12):1261-71
references.pmid: 22230884
references.citation: Arch Biochem Biophys. 2013 Jun;534(1-2):3-10
references.pmid: 23111185
references.citation: Am J Hum Genet. 2004 Dec;75(6):1079-93
references.pmid: 15492925
references.citation: Front Pediatr. 2014 Jun 03;2:52
references.pmid: 24918098
references.citation: Nature. 2013 Sep 19;501(7467):373-9
references.pmid: 23995685
references.citation: Sci Transl Med. 2012 Mar 7;4(124):124ra29
references.pmid: 22344463
references.citation: Nat Methods. 2012 Jun;9(6):575-8
references.pmid: 22484851
references.citation: Hum Mol Genet. 2014 Jul 1;23(13):3523-36
references.pmid: 24524897
references.citation: Cell. 2015 Dec 3;163(6):1314-25
references.pmid: 26638068
references.citation: J Biomol Screen. 2014 Jan;19(1):32-43
references.pmid: 24019252
references.citation: Nature. 2015 Nov 5;527(7576):95-9
references.pmid: 26524527
references.citation: Hum Mol Genet. 2005 Jul 15;14(14):1935-46
references.pmid: 15917271
references.citation: Dis Model Mech. 2013 Jul;6(4):896-904
references.pmid: 23751357
references.citation: Mol Psychiatry. 2016 Jan;21(1):49-61
references.pmid: 26503761
references.citation: J Med Chem. 2014 Dec 11;57(23 ):9776-95
references.pmid: 25441013
references.citation: Front Neurol. 2015 Mar 05;6:44
references.pmid: 25798128
references.citation: Cell. 2010 Nov 12;143(4):527-39
references.pmid: 21074045
references.citation: Nat Rev Genet. 2012 Jul 10;13(8):537-51
references.pmid: 22777127
references.citation: Nat Methods. 2015 Jul;12(7):671-8
references.pmid: 26005811
references.citation: Dev Biol. 2013 Feb 1;374(1):32-45
references.pmid: 23219959
references.citation: Nat Med. 2011 May;17(5):559-65
references.pmid: 21516088
references.citation: Neuron. 2011 Jul 14;71(1):35-48
references.pmid: 21745636
references.citation: ACS Chem Biol. 2014 Nov 21;9(11):2594-602
references.pmid: 25188731
references.citation: Cell Stem Cell. 2013 Dec 5;13(6):691-705
references.pmid: 24315443
references.citation: Mol Cell Neurosci. 2016 Jun;73:43-51
references.pmid: 26640241
references.citation: Cell Stem Cell. 2015 Aug 6;17(2):204-12
references.pmid: 26253202
references.citation: Am J Hum Genet. 2003 Jun;72(6):1401-11
references.pmid: 12736870
references.citation: Mol Cell Neurosci. 2016 Jun;73:63-83
references.pmid: 26608002
references.citation: Transl Psychiatry. 2014 Mar 25;4:e375
references.pmid: 25116795
references.citation: Sci Transl Med. 2012 Jul 4;4(141):141ra90
references.pmid: 22764206
references.citation: Cell. 2014 Jun 5;157(6):1262-78
references.pmid: 24906146
references.citation: Nat Commun. 2014 Mar 11;5:3339
references.pmid: 24618891
references.citation: Nature. 2011 May 12;473(7346):221-5
references.pmid: 21490598
references.citation: J Neurol Psychiatry. 1943 Jul;6(3-4):154-7
references.pmid: 21611430
references.citation: Assay Drug Dev Technol. 2014 Nov-Dec;12(9-10):536-47
references.pmid: 25506803
references.citation: Mol Autism. 2011 Feb 08;2(1):2
references.pmid: 21303513
references.citation: Mol Psychiatry. 2015 May;20(5):573-84
references.pmid: 25623948
references.citation: Nat Methods. 2015 Sep;12(9):885-92
references.pmid: 26237226
references.citation: Transl Psychiatry. 2014 Aug 26;4:e428
references.pmid: 25158003
references.citation: Nat Rev Neurol. 2015 Jun;11(6):339-50
references.pmid: 25986505
references.citation: Eur J Hum Genet. 2015 Feb;23(2):195-201
references.pmid: 24916645
references.citation: Nature. 2014 Feb 13;506(7487):185-90
references.pmid: 24463508
references.citation: PLoS One. 2015 Feb 17;10(2):e0118020
references.pmid: 25689802
references.citation: Stem Cell Rev. 2015 Oct;11(5):681-7
references.pmid: 26024842
references.citation: J Biomol Screen. 2015 Oct;20(9):1101-11
references.pmid: 26024946
references.citation: Trends Biochem Sci. 2006 Sep;31(9):533-40
references.pmid: 16829072
references.citation: J Biomol Screen. 2012 Oct;17(9):1252-63
references.pmid: 22923789
references.citation: Nat Genet. 2015 Feb;47(2):132-41
references.pmid: 25501393
references.citation: Nature. 2014 Nov 20;515(7527):414-8
references.pmid: 25132547
references.citation: J Neurosci. 2015 Nov 18;35(46):15295-306
references.pmid: 26586818
references.citation: J Neurogenet. 2011 Oct;25(3):88-103
references.pmid: 21797804
references.citation: Mol Psychiatry. 2015 Jun;20(6):703-17
references.pmid: 25733313
references.citation: Front Mol Neurosci. 2012 Jan 30;5:1
references.pmid: 22319467
references.citation: Eur J Hum Genet. 2011 Dec;19(12):1246-55
references.pmid: 21750574
references.citation: PLoS One. 2014 Nov 12;9(11):e112413
references.pmid: 25390032
references.citation: Nat Cell Biol. 2012 Sep;14(9):911-23
references.pmid: 22922712
references.citation: Stem Cell Reports. 2015 Jan 13;4(1):16-24
references.pmid: 25556567
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14169-74
references.pmid: 21807996
references.citation: Lancet Neurol. 2013 Feb;12(2):207-16
references.pmid: 23332364
references.citation: PLoS One. 2011;6(9):e25255
references.pmid: 21966470
references.citation: Proc Natl Acad Sci U S A. 2011 May 17;108(20):8299-304
references.pmid: 21525408
references.citation: Lancet. 2015 Oct 24;386(10004):1672-82
references.pmid: 26595641
references.citation: Nat Chem Biol. 2013 Nov;9(11):708-14
references.pmid: 24013279
references.citation: Nat Med. 2011 Nov 27;17 (12 ):1657-62
references.pmid: 22120178
references.citation: Stem Cells Transl Med. 2015 Jul;4(7):800-8
references.pmid: 25999519