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Induced pluripotent stem cells — opportunities for disease modelling and drug discovery

Key Points

  • Induced pluripotent stem cells (iPSCs) that are derived from patients and differentiated in vitro can provide disease-relevant cell types for drug screening.

  • Directed differentiation of iPSCs has yielded many disease-relevant cells — chiefly neurons, hepatocytes, blood cells and cardiomyocytes — but often the cells reflect embryonic stages of development, and may not faithfully reflect disease phenotypes of adult tissues.

  • Methods for deriving iPSCs are evolving, and much remains to be learned about the genetic and epigenetic stability of iPSCs and their relationships to embryonic stem cells, and how this affects the fidelity of drug screening.

  • Notwithstanding a few exceptions, disease modelling so far has focused on Mendelian disorders of high clinical penetrance and with a recognized cellular pathophysiology, such as spinal muscular atrophy, familial dysautonomia, Rett syndrome, Hutchinson–Gilford progeria syndrome and long QT syndrome. Whether more complex, sporadically occurring disease entities can be modelled with iPSCs remains uncertain.

  • Cell-based assays enable the discovery of novel pathways and the identification of compounds with favourable cell permeability and toxicity profiles, but such assays are less amenable to defining the structure–activity relationships that are important for optimizing drug properties.

  • iPSCs offer important advantages for drug toxicity screening against relevant human cells and tissues, and may facilitate the development of 'in vitro clinical trials' to test the efficacy of drugs or gene correction vectors against various distinct patient genotypes.

Abstract

The ability to generate induced pluripotent stem cells (iPSCs) from patients, and an increasingly refined capacity to differentiate these iPSCs into disease-relevant cell types, promises a new paradigm in drug development — one that positions human disease pathophysiology at the core of preclinical drug discovery. Disease models derived from iPSCs that manifest cellular disease phenotypes have been established for several monogenic diseases, but iPSCs can likewise be used for phenotype-based drug screens in complex diseases for which the underlying genetic mechanism is unknown. Here, we highlight recent advances as well as limitations in the use of iPSC technology for modelling a 'disease in a dish' and for testing compounds against human disease phenotypes in vitro. We discuss how iPSCs are being exploited to illuminate disease pathophysiology, identify novel drug targets and enhance the probability of clinical success of new drugs.

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Figure 1: An integrated model for drug discovery and development based on the iPSC technology platform.
Figure 2: Value creation with the iPSC-based drug discovery paradigm: comparison between conventional target-centric drug discovery and patient-derived iPSC-enabled drug discovery.
Figure 3: Schematic diagram of the iPSC-driven lead discovery platform based on iPierian's SMA programme.

References

  1. Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nature Rev. Drug Discov. 5, 835–844 (2006).

    CAS  Article  Google Scholar 

  2. Hazuda, D. J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646–650 (2000).

    CAS  Article  PubMed  Google Scholar 

  3. Jacoby, E., Bouhelal, R., Gerspacher, M. & Seuwen, K. The 7 TM G-protein-coupled receptor target family. ChemMedChem 1, 761–782 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Pouton, C. W. & Haynes, J. M. Embryonic stem cells as a source of models for drug discovery. Nature Rev. Drug Discov. 6, 605–616 (2007).

    CAS  Article  Google Scholar 

  5. Murry, C. E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).

    CAS  Article  PubMed  Google Scholar 

  6. Davila, J. C. et al. Use and application of stem cells in toxicology. Toxicol. Sci. 79, 214–223 (2004).

    CAS  Article  PubMed  Google Scholar 

  7. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). This was the first demonstration that mouse somatic cells can be reprogrammed into PSCs following the introduction of a defined set of transcription factors.

    CAS  Article  PubMed  Google Scholar 

  8. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    CAS  Article  PubMed  Google Scholar 

  9. Lowry, W. E. et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl Acad. Sci. USA 105, 2883–2888 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Park, I. H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008). This paper describes human iPSCs created from several diseases, including complex adult-onset diseases.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007). References 8, 9 and 11 were the first reports of the generation of iPSCs from human somatic cells by defined transcription factors.

    CAS  Article  PubMed  Google Scholar 

  12. Urbach, A., Bar-Nur, O., Daley, G. Q. & Benvenisty, N. Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6, 407–411 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Lee, G. et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461, 402–406 (2009). This work demonstrates that reprogrammed cells from patients with monogenic developmental diseases can recapitulate a disease-relevant phenotype, and that these disease phenotypes can be modified by drugs.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Carvajal-Vergara, X. et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465, 808–812 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Marchetto, M. C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Muotri, A. R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Zhang, J. et al. A human iPSC model of Hutchinson Gilford progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8, 31–45 (2011). This paper demonstrates that several disease-relevant cell types differentiated from reprogrammed cells (taken from patients) show disease phentoypes.

    CAS  Article  PubMed  Google Scholar 

  18. Moretti, A. et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363, 1397–1409 (2010).

    CAS  Article  PubMed  Google Scholar 

  19. Rashid, S. T. et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 120, 3127–3136 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Ebert, A. D. et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277–280 (2009). This work also demonstrates that reprogrammed cells from patients with monogenic developmental diseases can recapitulate a disease-relevant phenotype, and that these disease phenotypes can be modified by drugs.

    CAS  Article  PubMed  Google Scholar 

  21. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  Article  PubMed  Google Scholar 

  22. Keller, G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129–1155 (2005).

    CAS  Article  PubMed  Google Scholar 

  23. McNeish, J. et al. High-throughput screening in embryonic stem cell-derived neurons identifies potentiators of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate-type glutamate receptors. J. Biol. Chem. 285, 17209–17217 (2010). This was the first demonstration that cells differentiated from iPSCs can be used in high-throughput screens to discover new chemical entities.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Maitra, A. et al. Genomic alterations in cultured human embryonic stem cells. Nature Genet. 37, 1099–1103 (2005).

    CAS  Article  PubMed  Google Scholar 

  25. Baker, D. E. et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nature Biotech. 25, 207–215 (2007).

    CAS  Article  Google Scholar 

  26. Narva, E. et al. High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nature Biotech. 28, 371–377 (2010). This paper shows that chromosomal abnormalities accumulate during the passaging of human embryonic stem cells.

    Article  CAS  Google Scholar 

  27. Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).

    CAS  Article  PubMed  Google Scholar 

  28. Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55–70 (2007).

    CAS  Article  PubMed  Google Scholar 

  29. Blelloch, R., Venere, M., Yen, J. & Ramalho-Santos, M. Generation of induced pluripotent stem cells in the absence of drug selection. Cell Stem Cell 1, 245–247 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Meissner, A., Wernig, M. & Jaenisch, R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nature Biotech. 25, 1177–1181 (2007).

    CAS  Article  Google Scholar 

  31. Wernig, M., Meissner, A., Cassady, J. P. & Jaenisch, R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2, 10–12 (2008).

    CAS  Article  PubMed  Google Scholar 

  32. Boland, M. J. et al. Adult mice generated from induced pluripotent stem cells. Nature 461, 91–94 (2009).

    CAS  Article  PubMed  Google Scholar 

  33. Kang, L., Wang, J., Zhang, Y., Kou, Z. & Gao, S. iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell 5, 135–138 (2009).

    CAS  Article  PubMed  Google Scholar 

  34. Zhao, X. Y. et al. iPS cells produce viable mice through tetraploid complementation. Nature 461, 86–90 (2009). References 32–34 demonstrate the full developmental potential of mouse iPSCs through tetraploid complementation — the most stringent test of developmental potency.

    CAS  Article  PubMed  Google Scholar 

  35. Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008). This was the first demonstration that skin cells from patients can be reprogrammed and differentiated into disease-relevant cell types.

    CAS  Article  PubMed  Google Scholar 

  36. Loh, Y. H. et al. Reprogramming of T cells from human peripheral blood. Cell Stem Cell 7, 15–19 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Loh, Y. H. et al. Generation of induced pluripotent stem cells from human blood. Blood 113, 5476–5479 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Rajesh, D. et al. Human lymphoblastoid B-cell lines reprogrammed to EBV-free induced pluripotent stem cells. Blood 118, 1797–1800 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Choi, S. M. et al. Reprogramming of EBV-immortalized B-lymphocyte cell lines into induced pluripotent stem cells. Blood 118, 1801–1805 (2011). References 38 and 39 first reported the generation of iPSCs from immortalized blood cell lines, providing the opportunity to obtain patient cells from biobanks.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Sommer, C. A. et al. Excision of reprogramming transgenes improves the differentiation potential of iPS cells generated with a single excisable vector. Stem Cells 28, 64–74 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Si-Tayeb, K. et al. Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev. Biol. 10, 81 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T. & Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949–953 (2008).

    CAS  Article  PubMed  Google Scholar 

  43. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. & Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science 322, 945–949 (2008). References 42 and 43 were the first reports of reprogramming using vectors that are not integrated into the genome.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Okita, K. et al. A more efficient method to generate integration-free human iPS cells. Nature Methods 8, 409–412 (2011).

    CAS  Article  PubMed  Google Scholar 

  46. Kaji, K. et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458, 771–775 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Lacoste, A., Berenshteyn, F. & Brivanlou, A. H. An efficient and reversible transposable system for gene delivery and lineage-specific differentiation in human embryonic stem cells. Cell Stem Cell 5, 332–342 (2009).

    CAS  Article  PubMed  Google Scholar 

  48. Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Kim, D. et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4, 472–476 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Zhou, H. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381–384 (2009).

    CAS  Article  PubMed  Google Scholar 

  51. Cho, H. J. et al. Induction of pluripotent stem cells from adult somatic cells by protein-based reprogramming without genetic manipulation. Blood 116, 386–395 (2010).

    CAS  Article  PubMed  Google Scholar 

  52. Fusaki, N., Ban, H., Nishiyama, A., Saeki, K. & Hasegawa, M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 85, 348–362 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Seki, T. et al. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7, 11–14 (2010).

    CAS  Article  PubMed  Google Scholar 

  54. Nishimura, K. et al. Development of defective and persistent sendai virus vector: a unique gene delivery/expression system ideal for cell reprogramming. J. Biol. Chem. 286, 4760–4771 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yakubov, E., Rechavi, G., Rozenblatt, S. & Givol, D. Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors. Biochem. Biophys. Res. Commun. 394, 189–193 (2010).

    CAS  Article  PubMed  Google Scholar 

  56. Warren, L. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618–630 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Maehr, R. et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc. Natl Acad. Sci. USA 106, 15768–15773 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Desponts, C. & Ding, S. Using small molecules to improve generation of induced pluripotent stem cells from somatic cells. Methods Mol. Biol. 636, 207–218 (2010).

    CAS  Article  PubMed  Google Scholar 

  59. Li, W. & Ding, S. Small molecules that modulate embryonic stem cell fate and somatic cell reprogramming. Trends Pharmacol. Sci. 31, 36–45 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Chen, J. et al. BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone. Cell Res. 21, 205–212 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhu, S. et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7, 651–655 (2010).

    CAS  Article  PubMed  Google Scholar 

  62. Aalto-Setala, K., Conklin, B. R. & Lo, B. Obtaining consent for future research with induced pluripotent cells: opportunities and challenges. PLoS Biol. 7, e42 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Chou, B. K. et al. Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Res. 21, 518–529 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Hu, K. et al. Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 117, e109–e119 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Polo, J. M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotech. 28, 848–855 (2010).

    CAS  Article  Google Scholar 

  67. Bar-Nur, O., Russ, H. A., Efrat, S. & Benvenisty, N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet β cells. Cell Stem Cell 9, 17–23 (2011).

    CAS  Article  PubMed  Google Scholar 

  68. Ohi, Y. et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nature Cell Biol. 13, 541–549 (2011).

    CAS  Article  PubMed  Google Scholar 

  69. Ghosh, Z. et al. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS ONE 5, e8975 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hu, B. Y. et al. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl Acad. Sci. USA 107, 4335–4340 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Hanna, J. et al. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc. Natl Acad. Sci. USA 107, 9222–9227 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Bock, C. et al. Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144, 439–452 (2011). This paper describes the generation of an assay to predict the differentiation efficiency of distinct iPSC clones, providing a tool for quality control of such iPSC clones.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Boulting, G. L. et al. A functionally characterized test set of human induced pluripotent stem cells. Nature Biotech. 29, 279–286 (2011).

    CAS  Article  Google Scholar 

  74. Kattman, S. J. et al. Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8, 228–240 (2011).

    CAS  Article  PubMed  Google Scholar 

  75. Liu, L. et al. Activation of the imprinted Dlk1-Dio3 region correlates with pluripotency levels of mouse stem cells. J. Biol. Chem. 285, 19483–19490 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Stadtfeld, M. et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175–181 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Mayshar, Y. et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521–531 (2010).

    CAS  Article  PubMed  Google Scholar 

  78. Pasi, C. E. et al. Genomic instability in induced stem cells. Cell Death. Differ. 18, 745–753 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Laurent, L. C. et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106–118 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Hussein, S. M. et al. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62 (2011). This study demonstrates that reprogramming leads to an increase in copy number variation that is selected against and disappears after prolonged passaging of iPSCs.

    CAS  Article  PubMed  Google Scholar 

  82. Blum, B. & Benvenisty, N. The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8, 3822–3830 (2009).

    CAS  Article  PubMed  Google Scholar 

  83. Enver, T. et al. Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum. Mol. Genet. 14, 3129–3140 (2005).

    CAS  Article  PubMed  Google Scholar 

  84. Watanabe, K. et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nature Biotech. 25, 681–686 (2007).

    CAS  Article  Google Scholar 

  85. Svendsen, C. N. et al. A new method for the rapid and long term growth of human neural precursor cells. J. Neurosci. Methods 85, 141–152 (1998).

    CAS  Article  PubMed  Google Scholar 

  86. Chambers, S. M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotech. 27, 275–280 (2009).

    CAS  Article  Google Scholar 

  87. Soldner, F. et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Osakada, F. et al. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. J. Cell Sci. 122, 3169–3179 (2009).

    CAS  Article  PubMed  Google Scholar 

  89. Sullivan, G. J. et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 51, 329–335 (2010).

    CAS  Article  PubMed  Google Scholar 

  90. Choi, K. D. et al. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells 27, 559–567 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Ye, Z. et al. Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 114, 5473–5480 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Taura, D. et al. Adipogenic differentiation of human induced pluripotent stem cells: comparison with that of human embryonic stem cells. FEBS Lett. 583, 1029–1033 (2009).

    CAS  Article  PubMed  Google Scholar 

  93. Friling, S. et al. Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells. Proc. Natl Acad. Sci. USA 106, 7613–7618 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Hester, M. E. et al. Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol. Ther. 19, 1905–1912 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. Panman, L. et al. Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells. Cell Stem Cell 8, 663–675 (2011). References 93–95 describe improvements in the differentiation of iPSCs using lineage-specific transcription factors.

    CAS  Article  PubMed  Google Scholar 

  96. Raya, A. et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460, 53–59 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Itzhaki, I. et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229 (2011).

    CAS  Article  PubMed  Google Scholar 

  98. Nguyen, H. N. et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267–280 (2011). Together with references 107 and 151, this study identifies disease-relevant phenotypes in reprogrammed cells from patients with adult-onset diseases.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. Burghes, A. H. & Beattie, C. E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nature Rev. Neurosci. 10, 597–609 (2009).

    CAS  Article  Google Scholar 

  100. Crawford, T. O. & Pardo, C. A. The neurobiology of childhood spinal muscular atrophy. Neurobiol. Dis. 3, 97–110 (1996).

    CAS  Article  PubMed  Google Scholar 

  101. Slaugenhaupt, S. A. et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet. 68, 598–605 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Hotta, A. et al. Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nature Methods 6, 370–376 (2009).

    CAS  Article  PubMed  Google Scholar 

  104. Hennekam, R. C. Hutchinson–Gilford progeria syndrome: review of the phenotype. Am. J. Med. Genet. A 140, 2603–2624 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Kannankeril, P., Roden, D. M. & Darbar, D. Drug-induced long QT syndrome. Pharmacol. Rev. 62, 760–781 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. Roden, D. M. Drug-induced prolongation of the QT interval. N. Engl. J. Med. 350, 1013–1022 (2004).

    CAS  Article  PubMed  Google Scholar 

  107. Seibler, P. et al. Mitochondrial parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J. Neurosci. 31, 5970–5976 (2011). Together with references 98 and 151, this study identifies disease-relevant phenotypes in reprogrammed cells from patients with adult-onset diseases.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Discov. 3, 711–715 (2004).

    CAS  Article  Google Scholar 

  109. Chong, C. R., Chen, X., Shi, L., Liu, J. O. & Sullivan, D. J. Jr. A clinical drug library screen identifies astemizole as an antimalarial agent. Nature Chem. Biol. 2, 415–416 (2006).

    CAS  Article  Google Scholar 

  110. Majercak, J. et al. LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease. Proc. Natl Acad. Sci. USA 103, 17967–17972 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. Zhou, H. et al. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe 4, 495–504 (2008).

    CAS  Article  PubMed  Google Scholar 

  112. Wysowski, D. K. & Swartz, L. Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002: the importance of reporting suspected reactions. Arch. Intern. Med. 165, 1363–1369 (2005).

    Article  PubMed  Google Scholar 

  113. Pearson, H. The bitterest pill. Nature 444, 532–533 (2006).

    CAS  Article  Google Scholar 

  114. Kola, I. The state of innovation in drug development. Clin. Pharmacol. Ther. 83, 227–230 (2008).

    CAS  Article  PubMed  Google Scholar 

  115. Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).

    CAS  Article  PubMed  Google Scholar 

  116. Tall, A. R., Yvan-Charvet, L. & Wang, N. The failure of torcetrapib: was it the molecule or the mechanism? Arterioscler. Thromb. Vasc. Biol. 27, 257–260 (2007).

    CAS  Article  PubMed  Google Scholar 

  117. Joy, T. R. & Hegele, R. A. The failure of torcetrapib: what have we learned? Br. J. Pharmacol. 154, 1379–1381 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. Diener, H. C. et al. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials. Stroke 39, 1751–1758 (2008).

    CAS  Article  PubMed  Google Scholar 

  119. Erondu, N. et al. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. Cell Metab. 4, 275–282 (2006).

    CAS  Article  PubMed  Google Scholar 

  120. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  121. Tebbey, P. W. & Rink, C. Target product profile: a renaissance for its definition and use. J. Med. Market. 9, 301–307 (2009).

    Article  Google Scholar 

  122. US Food and Drug Administration. Guidance For Industry And Review Staff: Target Product Profile — A Strategic Development Process Tool. FDA website [online], (2007).

  123. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    CAS  Article  PubMed  Google Scholar 

  124. Frumkin, T. et al. Human embryonic stem cells carrying mutations for severe genetic disorders. In Vitro Cell. Dev. Biol. Anim. 46, 327–336 (2010).

    Article  PubMed  Google Scholar 

  125. Tropel, P. et al. High-efficiency derivation of human embryonic stem cell lines following pre-implantation genetic diagnosis. In Vitro Cell. Dev. Biol. Anim. 46, 376–385 (2010).

    Article  PubMed  Google Scholar 

  126. Verlinsky, Y. et al. Human embryonic stem cell lines with genetic disorders. Reprod. Biomed. Online 10, 105–110 (2005).

    CAS  Article  PubMed  Google Scholar 

  127. Mateizel, I. et al. Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders. Hum. Reprod. 21, 503–511 (2006).

    CAS  Article  PubMed  Google Scholar 

  128. Marteyn, A. et al. Mutant human embryonic stem cells reveal neurite and synapse formation defects in type 1 myotonic dystrophy. Cell Stem Cell 8, 434–444 (2011).

    CAS  Article  PubMed  Google Scholar 

  129. Deleu, S. et al. Human cystic fibrosis embryonic stem cell lines derived on placental mesenchymal stromal cells. Reprod. Biomed. Online 18, 704–716 (2009).

    CAS  Article  PubMed  Google Scholar 

  130. Somers, A. et al. Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells 28, 1728–1740 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. Kazuki, Y. et al. Complete genetic correction of iPS cells from Duchenne muscular dystrophy. Mol. Ther. 18, 386–393 (2010).

    CAS  Article  PubMed  Google Scholar 

  132. Niclis, J. C. et al. Human embryonic stem cell models of Huntington disease. Reprod. Biomed. Online 19, 106–113 (2009).

    CAS  Article  PubMed  Google Scholar 

  133. Zhang, N., An, M. C., Montoro, D. & Ellerby, L. M. Characterization of human Huntington's disease cell model from induced pluripotent stem cells. PLoS Curr. 2, RRN1193 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Jang, J. et al. Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. Ann. Neurol. 70, 402–409 (2011).

    Article  PubMed  Google Scholar 

  135. Ho, J. C. et al. Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C. Aging 3, 380–390 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. Ghodsizadeh, A. et al. Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev. 6, 622–632 (2010).

    Article  Google Scholar 

  137. Agarwal, S. et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464, 292–296 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. Batista, L. F. et al. Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474, 399–402 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. Tolar, J. et al. Induced pluripotent stem cells from individuals with recessive dystrophic epidermolysis bullosa. J. Invest. Dermatol. 131, 848–856 (2011).

    CAS  Article  PubMed  Google Scholar 

  140. Itoh, M., Kiuru, M., Cairo, M. S. & Christiano, A. M. Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells. Proc. Natl Acad. Sci. USA 108, 8797–8802 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. Mitne-Neto, M. et al. Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Hum. Mol. Genet. 20, 3642–3652 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. Howden, S. E. et al. Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy. Proc. Natl Acad. Sci. USA 108, 6537–6542 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. Liu, G. H. et al. Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome. Nature 472, 221–225 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. Liu, G. H. et al. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell 8, 688–694 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. Khan, I. F. et al. Engineering of human pluripotent stem cells by AAV-mediated gene targeting. Mol. Ther. 18, 1192–1199 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. Tolar, J. et al. Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome). Blood 117, 839–847 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. Lemonnier, T. et al. Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells. Hum. Mol. Genet. 20, 3653–3666 (2011).

    CAS  Article  PubMed  Google Scholar 

  148. Hargus, G. et al. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc. Natl Acad. Sci. USA 107, 15921–15926 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. Swistowski, A. et al. Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 28, 1893–1904 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. Jin, Z. B. et al. Modeling retinal degeneration using patient-specific induced pluripotent stem cells. PLoS ONE 6, e17084 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. Brennand, K. J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011). Together with references 98 and 107, this study identifies disease-relevant phenotypes in reprogrammed cells from patients with adult-onset diseases.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. Zhang, S. et al. Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. Hum. Mol. Genet. 20, 3176–3187 (2011).

    CAS  Article  PubMed  Google Scholar 

  153. Zou, J. et al. Oxidase-deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease-mediated safe harbor targeting. Blood 117, 5561–5572 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotech. 26, 101–106 (2008).

    CAS  Article  Google Scholar 

  155. Anokye-Danso, F. et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8, 376–388 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. Zhou, W. & Freed, C. R. Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 27, 2667–2674 (2009).

    CAS  Article  PubMed  Google Scholar 

  157. Jia, F. et al. A nonviral minicircle vector for deriving human iPS cells. Nature Methods 7, 197–199 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. Miyoshi, N. et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8, 633–638 (2011).

    CAS  Article  PubMed  Google Scholar 

  159. Esteban, M. A. et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6, 71–79 (2010).

    CAS  Article  PubMed  Google Scholar 

  160. Lin, T. et al. A chemical platform for improved induction of human iPSCs. Nature Methods 6, 805–808 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. Mali, P. et al. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells 28, 713–720 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  162. Haase, A. et al. Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell 5, 434–441 (2009).

    CAS  Article  PubMed  Google Scholar 

  163. Eminli, S. et al. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nature Genet. 41, 968–976 (2009).

    CAS  Article  PubMed  Google Scholar 

  164. Giorgetti, A. et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5, 353–357 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. Lagarkova, M. A. et al. Induction of pluripotency in human endothelial cells resets epigenetic profile on genome scale. Cell Cycle 9, 937–946 (2010).

    CAS  Article  PubMed  Google Scholar 

  166. Sun, N. et al. Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc. Natl Acad. Sci. USA 106, 15720–15725 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. Aoki, T. et al. Generation of induced pluripotent stem cells from human adipose-derived stem cells without c-MYC. Tissue Eng. Part A 16, 2197–2206 (2010).

    CAS  Article  PubMed  Google Scholar 

  168. Aasen, T. et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nature Biotech. 26, 1276–1284 (2008).

    CAS  Article  Google Scholar 

  169. Carey, B. W. et al. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc. Natl Acad. Sci. USA 106, 157–162 (2009).

    CAS  Article  PubMed  Google Scholar 

  170. Li, W. et al. Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells 27, 2992–3000 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Kim, J. B. et al. Direct reprogramming of human neural stem cells by OCT4. Nature 28 Aug 2009 (doi:10.1038/nature08436).

    CAS  Article  PubMed  Google Scholar 

  172. Ruiz, S. et al. High-efficient generation of induced pluripotent stem cells from human astrocytes. PLoS ONE 5, e15526 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Liu, H., Ye, Z., Kim, Y., Sharkis, S. & Jang, Y. Y. Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 51, 1810–1819 (2010).

    CAS  Article  PubMed  Google Scholar 

  174. Li, C. et al. Pluripotency can be rapidly and efficiently induced in human amniotic fluid-derived cells. Hum. Mol. Genet. 18, 4340–4349 (2009).

    CAS  Article  PubMed  Google Scholar 

  175. Zhao, H. X. et al. Rapid and efficient reprogramming of human amnion-derived cells into pluripotency by three factors OCT4/SOX2/NANOG. Differentiation 80, 123–129 (2010).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to especially thank S. Irion, E. Vaisberg, I. Griswold-Prenner and C. Johnson for their crucial input and help with writing the manuscript. Special thanks to A. Rosenthal for his help in editing and integrating the manuscript, and M. Smith and B. Keon for their help with the graphic design.

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Correspondence to George Q. Daley.

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Marica Grskovic and Ashkan Javaherian are both employed by iPierian, and Berta Strulovici is a former employee. George Q. Daley is on the scientific advisory board of iPierian. All co-authors hold equity in the company, which uses induced pluripotent stem cells to develop drugs against neurodegenerative diseases.

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FURTHER INFORMATION

George Q. Daley's homepage

Coriell Institute for Medical Research

Guidelines for Clinical Translation of Stem Cells

International Haplotype Mapping project

iPierian website

Johns Hopkins Clinical Compound Collections

MicroSource Spectrum Collection

Prestwick Collection

Sigma-Aldrich Library of Pharmacologically Active Compounds

UK Biobank

Glossary

Embryonic stem cells

(ESCs). Pluripotent cells derived from a pre-implantation-stage embryo. These cells are capable of dividing without differentiating for a prolonged period in culture.

Induced pluripotent stem cells

(iPSCs). Pluripotent cells derived from differentiated somatic cells through treatment with exogenous factors.

Disease phenotype

A molecular, cellular or functional manifestation of a disease in patient-derived cells.

Pluripotent stem cells

(PSCs). Undifferentiated cells that have the ability to self-renew and the potential to differentiate into cells of the three primary germ layers: endoderm, mesoderm or ectoderm.

Embryoid bodies

Aggregates of cells derived from pluripotent cells, formed by growing pluripotent cells in suspension in the absence of self-renewal-promoting factors. Following their aggregation, these cells differentiate into various differentiated cell types partly recapitulating early embryonic development.

Reprogramming

The process by which a differentiated somatic cell acquires the features of a pluripotent stem cell or a differentiated cell of a different cell type.

Spinal muscular atrophy

A monogenic neurodevelopmental disorder in which a reduced level of survival of motor neuron (SMN) protein leads to the degeneration of motor neurons during childhood.

Epigenetic

A heritable change in gene expression that is not caused by the DNA sequence.

Copy number variations

Duplications or deletions in the genome that lead to variability in the number of genes.

LEOPARD syndrome

An autosomal dominant multisystem disease caused by a mutation in the gene encoding protein tyrosine phosphatase non-receptor type 11. The disease affects the skin as well as the skeletal and cardiovascular systems.

QT interval

A measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart.

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Grskovic, M., Javaherian, A., Strulovici, B. et al. Induced pluripotent stem cells — opportunities for disease modelling and drug discovery. Nat Rev Drug Discov 10, 915–929 (2011). https://doi.org/10.1038/nrd3577

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