Stem Cell Reviews and Reports

, Volume 14, Issue 3, pp 323–336 | Cite as

Genome Editing in Induced Pluripotent Stem Cells using CRISPR/Cas9

  • Ronen Ben Jehuda
  • Yuval Shemer
  • Ofer Binah


The development of the reprogramming technology led to generation of induced Pluripotent Stem Cells (iPSC) from a variety of somatic cells. Ever since, fast growing knowledge of different efficient protocols enabled the differentiation of these iPSCs into different cells types utilized for disease modeling. Indeed, iPSC-derived cells have been increasingly used for investigating molecular and cellular pathophysiological mechanisms underlying inherited diseases. However, a major barrier in the field of iPSC-based disease modeling relies on discriminating between the effects of the causative mutation and the genetic background of these cells. In the past decade, researchers have made great improvement in genome editing techniques, with one of the latest being CRISPR/Cas9. Using a single non-sequence specific protein combined with a small guiding RNA molecule, this state-of-the-art approach enables modifications of genes with high efficiency and accuracy. By so doing, this technique enables the generation of isogenic controls or isogenic mutated cell lines in order to focus on the pathologies caused by a specific mutation. In this article, we review the latest studies combining iPSC and CRISPR/Cas9 technologies for the investigation of the molecular and cellular mechanisms underlying inherited diseases including immunological, metabolic, hematological, neurodegenerative and cardiac diseases.




Compliance with ethical standards

Conflict of interest

None to declare.


  1. 1.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.CrossRefPubMedGoogle Scholar
  2. 2.
    Guenther, M. G., Frampton, G. M., Soldner, F., et al. (2010). Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell, 7(2), 249–257.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Zhao, M.-T., Chen, H., Liu, Q., et al. (2017). Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs. Proceedings of the National Academy of Sciences, 114(52), E11111–E11120.CrossRefGoogle Scholar
  4. 4.
    Dimos JT, Rodolfa KT, Niakan KK, et al. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. TL - 321. Science;321 VN-(5893):1218–21.Google Scholar
  5. 5.
    Novak, A., Barad, L., Lorber, A., et al. (2015). Functional abnormalities in iPSC-derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations. Journal of Cellular and Molecular Medicine, 19(8), 2006–2018.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ben Jehuda, R., Eisen, B., Shemer, Y., et al. (2018). CRISPR correction of the PRKAG2 gene mutation in the patient’s induced pluripotent stem cell-derived cardiomyocytes eliminates electrophysiological and structural abnormalities. Heart Rhythm, 15(2), 267–276.CrossRefPubMedGoogle Scholar
  7. 7.
    Jung, C. B., & Moretti, A. (2012). Mederos y Schnitzler M, et al. Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Molecular Medicine, 4(3), 180–191.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Soldner, F., Hockemeyer, D., Beard, C., et al. (2009). Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136(5), 964–977.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Maehr, R., Chen, S., Snitow, M., et al. (2009). Generation of pluripotent stem cells from patients with type 1 diabetes. Proceedings of the National Academy of Sciences of the United States of America, 106(37), 15768–15773.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Carlson, C., Koonce, C., Aoyama, N., et al. (2013). Phenotypic screening with human IPS cell-derived cardiomyocytes: HTS-compatible assays for interrogating cardiac hypertrophy. Journal of Biomolecular Screening, 18(10), 1203–1211.CrossRefPubMedGoogle Scholar
  11. 11.
    Sander, J. D., & Joung, J. K. (2014). CRISPR-Cas systems for editing, regulating and targeting genomes. Nature Biotechnology, 32(4), 347–355.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Boch, J., Scholze, H., Schornack, S., et al. (2009). Breaking the code of DNA binding specificity of TAL-type III effectors. Science, 326(5959), 1509–1512.CrossRefPubMedGoogle Scholar
  13. 13.
    Liu, Q., Segal, D. J., Ghiara, J. B., & Barbas, C. F. (1997). Design of polydactyl zinc-finger proteins for unique addressing within complex genomes. Proceedings of the National Academy of Sciences, 94(11), 5525–5530.CrossRefGoogle Scholar
  14. 14.
    Sanjana, N. E., Cong, L., Zhou, Y., Cunniff, M. M., Feng, G., & Zhang, F. (2012). A transcription activator-like effector toolbox for genome engineering. Nature Protocols, 7(1), 171–192.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ran, F. A., Hsu, P. D., Lin, C. Y., et al. (2013a). Double nicking by RNA-guided CRISPR cas9 for enhanced genome editing specificity. Cell, 154(6), 1380–1389.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yin, H., Xue, W., Chen, S., et al. (2014). Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nature Biotechnology, 32(6), 551–553.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wu, Y., Liang, D., Wang, Y., et al. (2013). Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell Stem Cell, 13(6), 659–662.CrossRefPubMedGoogle Scholar
  18. 18.
    Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013b). Genome engineering using the CRISPR-Cas9 system. Nature Protocols, 8(11), 2281–2308.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wang, H., Yang, H., Shivalila, C. S., et al. (2013). One-step generation of mice carrying mutations in multiple genes by CRISPR/cas-mediated genome engineering. Cell, 153(4), 910–918.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cho, S. W., Kim, S., Kim, J. M., & Kim, J.-S. (2013). Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nature Biotechnology, 31(3), 230–232.CrossRefPubMedGoogle Scholar
  21. 21.
    Chang, N., Sun, C., Gao, L., et al. (2013). Genome editing with RNA-guided Cas9 nuclease in Zebrafish embryos. Nature Publishing Group, 23(4), 465–472.Google Scholar
  22. 22.
    Barrangou, R., Fremaux, C., Deveau, H., et al. (2007). CRISPR Provides Acquired Resistance Against Viruses in Prokaryotes. Science, 315(5819), 1709–1712.CrossRefPubMedGoogle Scholar
  23. 23.
    Makarova, K. S., Haft, D. H., Barrangou, R., et al. (2011). Evolution and classification of the CRISPR–Cas systems. Nature Reviews Microbiology, 9(6), 467–477.CrossRefPubMedGoogle Scholar
  24. 24.
    Brouns, S. J. J., Jore, M. M., Lundgren, M., et al. (2008). Small CRISPR RNAs guide antiviral defense in prokaryotes. Science, 321(5891), 960–964.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cong, L., Ran, F. A., Cox, D., et al. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science, 339(6121), 819–823.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hale, C. R., Majumdar, S., Elmore, J., et al. (2012). Essential features and rational design of CRISPR RNAs that function with the Cas RAMP module complex to cleave RNAs. Molecular Cell, 45(3), 292–302.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Deltcheva, E., Chylinski, K., Sharma, C. M., et al. (2011). CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature, 471(7340), 602–607.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gasiunas, G., Barrangou, R., Horvath, P., & Siksnys, V. (2012). Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proceedings of the National Academy of Sciences, 109(39), E2579–E2586.CrossRefGoogle Scholar
  29. 29.
    Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012). A programmable dual-RNA – guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096), 816–822.CrossRefPubMedGoogle Scholar
  30. 30.
    Sapranauskas, R., Gasiunas, G., Fremaux, C., Barrangou, R., Horvath, P., & Siksnys, V. (2011). The Streptococcus thermophilus CRISPR/Cas system provides immunity in Escherichia coli. Nucleic Acids Research, 39(21), 9275–9282.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Horii, T., Tamura, D., Morita, S., Kimura, M., & Hatada, I. (2013). Generation of an ICF syndrome model by efficient genome editing of human induced pluripotent stem cells using the CRISPR system. International Journal of Molecular Sciences, 14(10), 19774–19781.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Xu, G.-L., Bestor, T. H., Bourc’his, D., et al. (1999). Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature, 402(6758), 187–191.CrossRefPubMedGoogle Scholar
  33. 33.
    Tuck-Muller, C. M., Narayan, A., Tsien, F., et al. (2000). DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients. Cytogenetics and Cell Genetics, 89(1–2), 121–128.CrossRefPubMedGoogle Scholar
  34. 34.
    Pattanayak, V., Lin, S., Guilinger, J. P., Ma, E., Doudna, J. A., & Liu, D. R. (2013). High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity. Nature Biotechnology, 31(9), 839–843.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Shinkuma, S., Guo, Z., & Christiano, A. M. (2016). Site-specific genome editing for correction of induced pluripotent stem cells derived from dominant dystrophic epidermolysis bullosa. Proceedings of the National Academy of Sciences, 113(20), 5676–5681.CrossRefGoogle Scholar
  36. 36.
    Fine, J. D., Eady, R. A. J., Bauer, E. A., et al. (2008). The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. Journal of the American Academy of Dermatology, 58(6), 931–950.CrossRefPubMedGoogle Scholar
  37. 37.
    Shinkuma, S., McMillan, J. R., & Shimizu, H. (2011). Ultrastructure and molecular pathogenesis of epidermolysis bullosa. Clinics in Dermatology, 29(4), 412–419.CrossRefPubMedGoogle Scholar
  38. 38.
    Gupta, R. M., Meissner, T. B., Cowan, C. A., & Musunuru, K. (2016). Genome-edited human pluripotent stem cell-derived macrophages as a model of reverse cholesterol transport-brief report. Arteriosclerosis, Thrombosis, and Vascular Biology, 36(1), 15–18.PubMedGoogle Scholar
  39. 39.
    Oram, J. F., Lawn, R. M., Garvin, M. R., & Wade, D. P. (2000). ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. The Journal of Biological Chemistry, 275(44), 34508–34511.CrossRefPubMedGoogle Scholar
  40. 40.
    Bodzioch, M., Orsó, E., Klucken, J., et al. (1999). The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nature Genetics, 22(4), 347–351.CrossRefPubMedGoogle Scholar
  41. 41.
    Marczenke, M., Piccini, I., Mengarelli, I., et al. (2017). Cardiac subtype-specific modeling of Kv1.5 ion channel deficiency using human pluripotent stem cells. Frontiers in Physiology, 8(JUL), 1–11.Google Scholar
  42. 42.
    Schmitt, N., Grunnet, M., & Olesen, S.-P. (2014). Cardiac potassium channel subtypes: new roles in repolarization and arrhythmia. Physiological Reviews, 94(2), 609–653.CrossRefPubMedGoogle Scholar
  43. 43.
    Olson, T. M., Alekseev, A. E., Liu, X. K., et al. (2006). Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Human Molecular Genetics, 15(14), 2185–2191.CrossRefPubMedGoogle Scholar
  44. 44.
    Park, C. Y., Halevy, T., Lee, D. R., et al. (2015). Reversion of FMR1 methylation and silencing by editing the triplet repeats in fragile X iPSC-derived neurons. Cell Reports, 13(2), 234–241.CrossRefPubMedGoogle Scholar
  45. 45.
    Crawford, D. C., Acuña, J. M., & Sherman, S. L. (2001). FMR1 and the fragile X syndrome: human genome epidemiology review. Genetics in Medicine, 3(5), 359–371.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Young, C. S., Hicks, M. R., Ermolova, N. V., et al. (2016). A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell, 18(4), 533–540.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bushby, K., Finkel, R., Birnkrant, D. J., et al. (2010). Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurology, 9(1), 77–93.CrossRefPubMedGoogle Scholar
  48. 48.
    Béroud, C., Tuffery-Giraud, S., Matsuo, M., et al. (2007). Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Human Mutation, 28(2), 196–202.CrossRefPubMedGoogle Scholar
  49. 49.
    Echigoya, Y., Aoki, Y., Miskew, B., et al. (2015). Long-term efficacy of systemic multiexon skipping targeting Dystrophin exons 45–55 with a cocktail of vivo-morpholinos in Mdx52 mice. Molecular Therapy--Nucleic Acids, 4(2).Google Scholar
  50. 50.
    Kim, B. Y., Jeong, S. K., Lee, S. Y., et al. (2016). Concurrent progress of reprogramming and gene correction to overcome therapeutic limitation of mutant ALK2-iPSC. Experimental & Molecular Medicine, 48(6), e237–e212.CrossRefGoogle Scholar
  51. 51.
    Nayler, S., Gatei, M., Kozlov, S., et al. (2012). Induced pluripotent stem cells from Ataxia-Telangiectasia recapitulate the cellular phenotype. Stem Cells Translational Medicine, 1(7), 523–535.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Raya, Á., Rodríguez-Piz, I., Guenechea, G., et al. (2009). Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature, 460(7251), 53–59.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hamasaki, M., Hashizume, Y., Yamada, Y., et al. (2012). Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: Mechanisms of reprogramming and strategy for drug identification. Stem Cells, 30(11), 2437–2449.CrossRefPubMedGoogle Scholar
  54. 54.
    Shore, E. M., Xu, M., Feldman, G. J., Fenstermacher, D. A., Brown, M. A., & Kaplan, F. S. (2006). A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics, 38(5), 525–527.CrossRefPubMedGoogle Scholar
  55. 55.
    Flynn, R., Grundmann, A., Renz, P., et al. (2015). CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells. Experimental Hematology, 43(10), 838–848.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Segal, B. H., Leto, T. L., Gallin, J. I., Malech, H. L., & Holland, S. M. (2000). Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine, 79(3), 170–200.CrossRefPubMedGoogle Scholar
  57. 57.
    Stein, S., Ott, M. G., Schultze-Strasser, S., et al. (2010). Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nature Medicine, 16(2), 198–204.CrossRefPubMedGoogle Scholar
  58. 58.
    Holland, S. M. (2010). Chronic granulomatous disease. Clinical Reviews in Allergy and Immunology, 38(1), 3–10.CrossRefPubMedGoogle Scholar
  59. 59.
    Wang, L., Yi, F., Fu, L., et al. (2017). CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs. Protein & Cell, 8(5), 365–378.CrossRefGoogle Scholar
  60. 60.
    Serio A, Patani R. (2017) Concise review: the cellular conspiracy of amyotrophic lateral sclerosis. Stem CellsGoogle Scholar
  61. 61.
    Rosen, D. R., Siddique, T., Patterson, D., et al. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362(6415), 59–62.CrossRefPubMedGoogle Scholar
  62. 62.
    Zhang, Y., Schmid, B., Nikolaisen, N. K., et al. (2017). Patient iPSC-derived neurons for disease modeling of frontotemporal dementia with mutation in CHMP2B. Stem Cell Reports, 8(3), 648–658.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Rossor, M. N., Fox, N. C., Mummery, C. J., Schott, J. M., & Warren, J. D. (2010). The diagnosis of young-onset dementia. Lancet Neurology, 9(8), 793–806.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Chassefeyre, R., Martinez-Hernandez, J., Bertaso, F., et al. (2015). Regulation of postsynaptic function by the dementia-related ESCRT-III subunit CHMP2B. The Journal of Neuroscience, 35(7), 3155–3173.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Isaacs, A. M., Johannsen, P., Holm, I., et al. (2011). Frontotemporal dementia caused by CHMP2B mutations. Current Alzheimer Research, 8, 246–251.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Liu, Y., Conlon, D. M., Bi, X., et al. (2017). Lack of MTTP activity in pluripotent stem cell-derived hepatocytes and cardiomyocytes abolishes apoB secretion and increases cell stress. Cell Reports, 19(7), 1456–1466.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    DJ, R., & Brewer Jr., H. (1993). Abetalipoproteinemia: New insights into lipoprotein assembly and vitamin e metabolism from a rare genetic disease. JAMA, 270(7), 865–869.CrossRefGoogle Scholar
  68. 68.
    Dische, M. R., & Porro, R. S. (1970). The cardiac lesions in Bassen-Kornzweig syndrome. Report of a case, with autopsy findings. The American Journal of Medicine, 49(4), 568–571.CrossRefPubMedGoogle Scholar
  69. 69.
    Ledmyr, H., McMahon, A. D., Ehrenborg, E., et al. (2004). The microsomal triglyceride transfer protein gene-493 T variant lowers cholesterol but increases the risk of coronary heart disease. Circulation, 109(19), 2279–2284.CrossRefPubMedGoogle Scholar
  70. 70.
    Zhang, L.-P., Hui, B., & Gao, B.-R. (2010). High risk of sudden death associated with a PRKAG2-related familial Wolff-Parkinson-White syndrome. Journal of Electrocardiology, 44(4), 483–486.CrossRefPubMedGoogle Scholar
  71. 71.
    Scott, J. W., Hawley, S. A., Green, K. A., et al. (2004). CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. The Journal of Clinical Investigation, 113(2), 274–284.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Zou, L., Shen, M., Arad, M., et al. (2005). N488I mutation of the γ2-subunit results in bidirectional changes in AMP-activated protein kinase activity. Circulation Research, 97(4), 323–328.CrossRefPubMedGoogle Scholar
  73. 73.
    Xie, F., Ye, L., Chang, J. C., et al. (2014). Seamless gene correction of β-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac. Genome Research, 24(9), 1526–1533.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Cavazzana-Calvo, M., Payen, E., Negre, O., et al. (2010). Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature, 467(7313), 318–322.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., et al. (2003). LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science, 302(5644), 415–419.CrossRefPubMedGoogle Scholar
  76. 76.
    Woods, N. B., Bottero, V., Schmidt, M., Von Kalle, C., & Verma, I. M. (2006). Gene therapy: Therapeutic gene causing lymphoma. Nature, 440(7088), 1123.CrossRefPubMedGoogle Scholar
  77. 77.
    Miyaoka, Y., Chan, A. H., Judge, L. M., et al. (2014). Isolation of single-base genome-edited human iPS cells without antibiotic selection. Nature Methods, 11(3), 291–293.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Liang, P., Sallam, K., Wu, H., et al. (2017). Patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes elucidate single cell phenotype of Brugada Syndrome. Journal of the American College of Cardiology, 68(19), 2086–2096.CrossRefGoogle Scholar
  79. 79.
    Brugada, P., & Brugada, J. (1992). Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome. A multicenter report. Journal of the American College of Cardiology, 20(6), 1391–1396.CrossRefPubMedGoogle Scholar
  80. 80.
    Brugada, J., Brugada, R., & Brugada, P. (2003). Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation, 108(25), 3092–3096.CrossRefPubMedGoogle Scholar
  81. 81.
    Xu, X., Tay, Y., Sim, B., et al. (2017). Reversal of phenotypic abnormalities by CRISPR/Cas9-mediated gene correction in Huntington disease patient-derived induced pluripotent stem cells. Stem Cell Reports, 8(3), 619–633.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    MacDonald, M. E., Ambrose, C. M., Duyao, M. P., et al. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 72(6), 971–983.CrossRefGoogle Scholar
  83. 83.
    Murakami, N., Imamura, K., Izumi, Y., et al. (2017). Proteasome impairment in neural cells derived from HMSN-P patient iPSCs. Molecular Brain, 10(1), 1–10.CrossRefGoogle Scholar
  84. 84.
    Ishiura, H., Sako, W., Yoshida, M., et al. (2012). The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. American Journal of Human Genetics, 91(2), 320–329.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Takashima, H., Nakagawa, M., Nakahara, K., et al. (1997). A new type of hereditary motor and sensory neuropathy linked to chromosome 3. Annals of Neurology, 41(6), 771–780.CrossRefPubMedGoogle Scholar
  86. 86.
    Ishikawa, T., Imamura, K., Kondo, T., et al. (2016). Genetic and pharmacological correction of aberrant dopamine synthesis using patient iPSCs with BH4 metabolism disorders. Human Molecular Genetics, 25(23), 5188–5197.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Longo, N. (2009). Disorders of biopterin metabolism. Journal of Inherited Metabolic Disease, 32(3), 333–342.CrossRefPubMedGoogle Scholar
  88. 88.
    Kang, H., Minder, P., Park, M. A., Mesquitta, W.-T., Torbett, B. E., & Slukvin, I. I. (2015). CCR5 disruption in induced pluripotent stem cells using CRISPR/Cas9 provides selective resistance of immune cells to CCR5-tropic HIV-1 virus. Molecular Therapy--Nucleic Acids, 4(October), e268.CrossRefPubMedGoogle Scholar
  89. 89.
    Samson, M., Labbe, O., Mollereau, C., Vassart, G., & Parmentier, M. (1996). Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry, 35(11), 3362–3367.CrossRefPubMedGoogle Scholar
  90. 90.
    Broder, C. C., & Collman, R. G. (1997). Chemokine receptors and HIV. Journal of Leukocyte Biology, 62(1), 20–29.CrossRefPubMedGoogle Scholar
  91. 91.
    Li, H. L., Fujimoto, N., Sasakawa, N., et al. (2015). Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Reports, 4(1), 143–154.CrossRefPubMedGoogle Scholar
  92. 92.
    Pichavant, C., Aartsma-Rus, A., Clemens, P. R., et al. (2011). Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Molecular Therapy, 19(5), 830–840.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Okada, T., & Takeda, S. (2013). Current challenges and future directions in recombinant AAV-mediated gene therapy of duchenne muscular dystrophy. Pharmaceuticals, 6(7), 813–836.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Aartsma-Rus, A., Fokkema, I., Verschuuren, J., et al. (2009). Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Human Mutation, 30(3), 293–299.CrossRefPubMedGoogle Scholar
  95. 95.
    Huang, X., Wang, Y., Yan, W., et al. (2015). Production of gene-corrected adult beta globin protein in human erythrocytes differentiated from patient iPSCs after genome editing of the sickle point mutation. Stem Cells, 33(5), 1470–1479.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Davis, R. P., Costa, M., Grandela, C., et al. (2008). A protocol for removal of antibiotic resistance cassettes from human embryonic stem cells genetically modified by homologous recombination or transgenesis. Nature Protocols, 3(10), 1550–1558.CrossRefPubMedGoogle Scholar
  97. 97.
    Smith, C., Abalde-Atristain, L., He, C., et al. (2015). Efficient and allele-specific genome editing of disease loci in human iPSCs. Molecular Therapy, 23(3), 570–577.CrossRefPubMedGoogle Scholar
  98. 98.
    Limpitikul, W. B., Dick, I. E., Tester, D. J., et al. (2017). A precision medicine approach to the rescue of function on malignant calmodulinopathic long-QT syndrome. Circulation Research, 120(1), 39–48.CrossRefPubMedGoogle Scholar
  99. 99.
    Goldenberg, I., Zareba, W., & Moss, A. J. (2008). Long QT Syndrome. Current Problems in Cardiology, 33(11), 629–694.CrossRefPubMedGoogle Scholar
  100. 100.
    Nakano, Y., & Shimizu, W. (2016). Genetics of long-QT syndrome. Journal of Human Genetics, 61(1), 51–55.CrossRefPubMedGoogle Scholar
  101. 101.
    Ackerman, M. J., Priori, S. G., Willems, S., et al. (2011). HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm, 8(8), 1308–1339.CrossRefPubMedGoogle Scholar
  102. 102.
    Dick, I. E., Joshi-Mukherjee, R., Yang, W., & Yue, D. T. (2016). Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca2 + −dependent inactivation. Nature Communications, 7, 1–12.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of MedicineTechnionHaifaIsrael
  2. 2.The Rappaport Institute, Rappaport Faculty of MedicineTechnionHaifaIsrael
  3. 3.Rappaport Faculty of MedicineTechnionHaifaIsrael
  4. 4.Department of BiotechnologyTechnionHaifaIsrael

Personalised recommendations