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Review article: Biomedical intelligence

Vol. 149 No. 0304 (2019)

A new era of gene editing for the treatment of human diseases

Cite this as:
Swiss Med Wkly. 2019;149:w20021


The treatment of human diseases using gene-editing technology has been envisioned for several decades with the realisation that so many were associated with mutations in DNA. The Human Genome Project opened new doors for identifying the genetic bases for human suffering. Research on gene editing has been active since the 1970s, but the technology has seen substantial growth and application just within the past decade. Simply stated, CRISPR technology has become a phenomenon in both biomedical and therapeutics research. Concurrently, cell therapies and pluripotent stem cell research have also been refined and now interfaced with CRISPR technology to enhance and maximise their potential in modelling as well as treatment of human diseases. In this review, we discuss the novel and revolutionary modality of gene editing, as this marks a new era in research and medicine. We also discuss gene-modifying technologies leading to CRISPR, as they are still being used for a wide variety of genomic applications. The modes and challenges for delivery of gene editing components are also discussed. Lastly, we review examples of human diseases that are not only amenable to gene editing techniques, but also show true promise of cure in the early 21st century of genetic correction and gene repair.


  1. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the human genome. Science. 2001;291(5507):1304–51. doi:.
  2. Weatherall DJ. Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet. 2001;2(4):245–55. doi:.
  3. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9(5):356–69. doi:.
  4. Theisen A, Shaffer LG. Disorders caused by chromosome abnormalities. Appl Clin Genet. 2010;3:159–74. doi:.
  5. Moosavi A, Motevalizadeh Ardekani A. Role of epigenetics in biology and human diseases. Iran Biomed J. 2016;20(5):246–58. doi:.
  6. Warton K, Mahon KL, Samimi G. Methylated circulating tumor DNA in blood: power in cancer prognosis and response. Endocr Relat Cancer. 2016;23(3):R157–71. doi:.
  7. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–63. doi:.
  8. Schiffer JT, Aubert M, Weber ND, Mintzer E, Stone D, Jerome KR. Targeted DNA mutagenesis for the cure of chronic viral infections. J Virol. 2012;86(17):8920–36. doi:.
  9. Smith HO, Wilcox KW. A restriction enzyme from Hemophilus influenzae. I. Purification and general properties. J Mol Biol. 1970;51(2):379–91. doi:.
  10. Friedmann T, Roblin R. Gene therapy for human genetic disease? Science. 1972;175(4025):949–55. doi:.
  11. Capecchi MR. Altering the genome by homologous recombination. Science. 1989;244(4910):1288–92. doi:.
  12. Smithies O, Gregg RG, Boggs SS, Koralewski MA, Kucherlapati RS. Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature. 1985;317(6034):230–4. doi:.
  13. Rudin N, Sugarman E, Haber JE. Genetic and physical analysis of double-strand break repair and recombination in Saccharomyces cerevisiae. Genetics. 1989;122(3):519–34.
  14. Rouet P, Smih F, Jasin M. Introduction of double-strand breaks into the genome of mouse cells by expression of a rare-cutting endonuclease. Mol Cell Biol. 1994;14(12):8096–106. doi:.
  15. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911. doi:.
  16. Lieber MR, Ma Y, Pannicke U, Schwarz K. Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol. 2003;4(9):712–20. doi:.
  17. Guirouilh-Barbat J, Huck S, Bertrand P, Pirzio L, Desmaze C, Sabatier L, et al. Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian cells. Mol Cell. 2004;14(5):611–23. doi:.
  18. Szostak JW, Orr-Weaver TL, Rothstein RJ, Stahl FW. The double-strand-break repair model for recombination. Cell. 1983;33(1):25–35. doi:.
  19. Plessis A, Perrin A, Haber JE, Dujon B. Site-specific recombination determined by I-SceI, a mitochondrial group I intron-encoded endonuclease expressed in the yeast nucleus. Genetics. 1992;130(3):451–60.
  20. Chevalier BS, Stoddard BL. Homing endonucleases: structural and functional insight into the catalysts of intron/intein mobility. Nucleic Acids Res. 2001;29(18):3757–74. doi:.
  21. Arnould S, Chames P, Perez C, Lacroix E, Duclert A, Epinat JC, et al. Engineering of large numbers of highly specific homing endonucleases that induce recombination on novel DNA targets. J Mol Biol. 2006;355(3):443–58. doi:.
  22. Stoddard BL. Homing endonuclease structure and function. Q Rev Biophys. 2005;38(1):49–95. doi:.
  23. Rosen LE, Morrison HA, Masri S, Brown MJ, Springstubb B, Sussman D, et al. Homing endonuclease I-CreI derivatives with novel DNA target specificities. Nucleic Acids Res. 2006;34(17):4791–800. doi:.
  24. Sussman D, Chadsey M, Fauce S, Engel A, Bruett A, Monnat R, Jr, et al. Isolation and characterization of new homing endonuclease specificities at individual target site positions. J Mol Biol. 2004;342(1):31–41. doi:.
  25. Klug A, Rhodes D. Zinc fingers: a novel protein fold for nucleic acid recognition. Cold Spring Harb Symp Quant Biol. 1987;52(0):473–82. doi:.
  26. Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci USA. 1996;93(3):1156–60. doi:.
  27. Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. Genome editing with engineered zinc finger nucleases. Nat Rev Genet. 2010;11(9):636–46. doi:.
  28. Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326(5959):1509–12. doi:.
  29. Sun N, Zhao H. Transcription activator-like effector nucleases (TALENs): a highly efficient and versatile tool for genome editing. Biotechnol Bioeng. 2013;110(7):1811–21. doi:.
  30. Miller JC, Tan S, Qiao G, Barlow KA, Wang J, Xia DF, et al. A TALE nuclease architecture for efficient genome editing. Nat Biotechnol. 2011;29(2):143–8. doi:.
  31. Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP, et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol. 2011;29(8):731–4. doi:.
  32. Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A. Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. J Bacteriol. 1987;169(12):5429–33. doi:.
  33. Mojica FJ, Díez-Villaseñor C, Soria E, Juez G. Biological significance of a family of regularly spaced repeats in the genomes of Archaea, Bacteria and mitochondria. Mol Microbiol. 2000;36(1):244–6. doi:.
  34. Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science. 2007;315(5819):1709–12. doi:.
  35. Garneau JE, Dupuis MÈ, Villion M, Romero DA, Barrangou R, Boyaval P, et al. The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Nature. 2010;468(7320):67–71. doi:.
  36. Horvath P, Barrangou R. CRISPR/Cas, the immune system of bacteria and archaea. Science. 2010;327(5962):167–70. doi:.
  37. Bolotin A, Quinquis B, Sorokin A, Ehrlich SD. Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin. Microbiology. 2005;151(8):2551–61. doi:.
  38. Wright AV, Nuñez JK, Doudna JA. Biology and applications of CRISPR systems: harnessing Nature’s toolbox for genome engineering. Cell. 2016;164(1-2):29–44. doi:.
  39. Mohanraju P, Makarova KS, Zetsche B, Zhang F, Koonin EV, van der Oost J. Diverse evolutionary roots and mechanistic variations of the CRISPR-Cas systems. Science. 2016;353(6299):aad5147. doi:.
  40. Makarova KS, Wolf YI, Alkhnbashi OS, Costa F, Shah SA, Saunders SJ, et al. An updated evolutionary classification of CRISPR-Cas systems. Nat Rev Microbiol. 2015;13(11):722–36. doi:.
  41. Sternberg SH, LaFrance B, Kaplan M, Doudna JA. Conformational control of DNA target cleavage by CRISPR-Cas9. Nature. 2015;527(7576):110–3. doi:.
  42. Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014;157(6):1262–78. doi:.
  43. Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096. doi:.
  44. Sapranauskas R, Gasiunas G, Fremaux C, Barrangou R, Horvath P, Siksnys V. The Streptococcus thermophilus CRISPR/Cas system provides immunity in Escherichia coli. Nucleic Acids Res. 2011;39(21):9275–82. doi:.
  45. Jinek M, East A, Cheng A, Lin S, Ma E, Doudna J. RNA-programmed genome editing in human cells. Weigel D, ed. eLife. 2013;2:e00471. doi:
  46. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819–23. doi:.
  47. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339(6121):823–6. doi:.
  48. Cho SW, Kim S, Kim JM, Kim JS. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat Biotechnol. 2013;31(3):230–2. doi:.
  49. Barrangou R, Doudna JA. Applications of CRISPR technologies in research and beyond. Nat Biotechnol. 2016;34(9):933–41. doi:.
  50. Lu XJ, Qi X, Zheng DH, Ji LJ. Modeling cancer processes with CRISPR-Cas9. Trends Biotechnol. 2015;33(6):317–9. doi:.
  51. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2013;152(5):1173–83. doi:.
  52. Tanenbaum ME, Gilbert LA, Qi LS, Weissman JS, Vale RD. A protein-tagging system for signal amplification in gene expression and fluorescence imaging. Cell. 2014;159(3):635–46. doi:.
  53. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464–71. doi:. Correction in: Nature. 2017;559:E8. doi:
  54. Hilton IB, D’Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33(5):510–7. doi:.
  55. Vojta A, Dobrinić P, Tadić V, Bočkor L, Korać P, Julg B, et al. Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res. 2016;44(12):5615–28. doi:.
  56. Liao H-K, Hatanaka F, Araoka T, Reddy P, Wu M-Z, Sui Y, et al. In vivo target gene activation via CRISPR/Cas9-mediated trans-epigenetic modulation. Cell. 2017;171(7):1495–1507.e15. doi:.
  57. Lino CA, Harper JC, Carney JP, Timlin JA. Delivering CRISPR: a review of the challenges and approaches. Drug Deliv. 2018;25(1):1234–57. doi:.
  58. Yang H, Wang H, Shivalila CS, Cheng AW, Shi L, Jaenisch R. One-step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering. Cell. 2013;154(6):1370–9. doi:.
  59. Wu Y, Zhou H, Fan X, Zhang Y, Zhang M, Wang Y, et al. Correction of a genetic disease by CRISPR-Cas9-mediated gene editing in mouse spermatogonial stem cells. Cell Res. 2015;25(1):67–79. doi:.
  60. Ye L, Wang J, Beyer AI, Teque F, Cradick TJ, Qi Z, et al. Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Δ32 mutation confers resistance to HIV infection. Proc Natl Acad Sci USA. 2014;111(26):9591–6. doi:.
  61. Wang J, Quake SR. RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection. Proc Natl Acad Sci USA. 2014;111(36):13157–62. doi:.
  62. Zuckermann M, Hovestadt V, Knobbe-Thomsen CB, Zapatka M, Northcott PA, Schramm K, et al. Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling. Nat Commun. 2015;6(1):7391. doi:.
  63. Yin H, Song CQ, Dorkin JR, Zhu LJ, Li Y, Wu Q, et al. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol. 2016;34(3):328–33. doi:.
  64. Han X, Liu Z, Jo MC, Zhang K, Li Y, Zeng Z, et al. CRISPR-Cas9 delivery to hard-to-transfect cells via membrane deformation. Sci Adv. 2015;1(7):e1500454. doi:.
  65. Chen X, Gonçalves MAFV. Engineered viruses as genome editing devices. Mol Ther. 2016;24(3):447–57. doi:.
  66. Biasco L, Baricordi C, Aiuti A. Retroviral integrations in gene therapy trials. Mol Ther. 2012;20(4):709–16. doi:.
  67. Mátrai J, Chuah MKL, VandenDriessche T. Recent advances in lentiviral vector development and applications. Mol Ther. 2010;18(3):477–90. doi:.
  68. Russell DW, Hirata RK. Human gene targeting by viral vectors. Nat Genet. 1998;18(4):325–30. doi:.
  69. Miller DG, Petek LM, Russell DW. Human gene targeting by adeno-associated virus vectors is enhanced by DNA double-strand breaks. Mol Cell Biol. 2003;23(10):3550–7. doi:.
  70. Samulski RJ, Zhu X, Xiao X, Brook JD, Housman DE, Epstein N, et al. Targeted integration of adeno-associated virus (AAV) into human chromosome 19. EMBO J. 1991;10(12):3941–50. doi:.
  71. Daya S, Berns KI. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev. 2008;21(4):583–93. doi:.
  72. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12(3):342–7. doi:.
  73. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357–65. doi:.
  74. Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371(21):1994–2004. doi:.
  75. George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377(23):2215–27. doi:.
  76. Huai C, Jia C, Sun R, Xu P, Min T, Wang Q, et al. CRISPR/Cas9-mediated somatic and germline gene correction to restore hemostasis in hemophilia B mice. Hum Genet. 2017;136(7):875–83. doi:.
  77. Ohmori T, Nagao Y, Mizukami H, Sakata A, Muramatsu SI, Ozawa K, et al. CRISPR/Cas9-mediated genome editing via postnatal administration of AAV vector cures haemophilia B mice. Sci Rep. 2017;7(1):4159. doi:.
  78. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377(26):2519–30. doi:.
  79. Park CY, Kim DH, Son JS, Sung JJ, Lee J, Bae S, et al. Functional correction of large factor VIII gene chromosomal inversions in hemophilia A patient-derived iPSCs using CRISPR-Cas9. Cell Stem Cell. 2015;17(2):213–20. doi:.
  80. Chiuchiolo MJ, Crystal RG. Gene therapy for alpha-1 antitrypsin deficiency lung disease. Ann Am Thorac Soc. 2016;13(Suppl 4):S352–69. doi:.
  81. Stephens CJ, Kashentseva E, Everett W, Kaliberova L, Curiel DT. Targeted in vivo knock-in of human alpha-1-antitrypsin cDNA using adenoviral delivery of CRISPR/Cas9. Gene Ther. 2018;25(2):139–56. doi:.
  82. Shen S, Sanchez ME, Blomenkamp K, Corcoran EM, Marco E, Yudkoff CJ, et al. Amelioration of alpha-1 antitrypsin deficiency diseases with genome editing in transgenic mice. Hum Gene Ther. 2018;29(8):861–73. doi:.
  83. Ginn SL, Amaya AK, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2017: An update. J Gene Med. 2018;20(5):e3015. doi:.
  84. Firth AL, Menon T, Parker GS, Qualls SJ, Lewis BM, Ke E, et al. Functional gene correction for cystic fibrosis in lung epithelial cells generated from patient iPSCs. Cell Rep. 2015;12(9):1385–90. doi:.
  85. Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013;13(6):653–8. doi:.
  86. Griesenbach U, Inoue M, Meng C, Farley R, Chan M, Newman NK, et al. Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy. Am J Respir Crit Care Med. 2012;186(9):846–56. doi:.
  87. Keswani SG, Balaji S, Le L, Leung A, Katz AB, Lim FY, et al. Pseudotyped AAV vector-mediated gene transfer in a human fetal trachea xenograft model: implications for in utero gene therapy for cystic fibrosis. PLoS One. 2012;7(8):e43633. doi:.
  88. Alton EW, Beekman JM, Boyd AC, Brand J, Carlon MS, Connolly MM, et al. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax. 2017;72(2):137–47. doi:.
  89. Ebina H, Misawa N, Kanemura Y, Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci Rep. 2013;3(1):2510. doi:.
  90. Liao HK, Gu Y, Diaz A, Marlett J, Takahashi Y, Li M, et al. Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells. Nat Commun. 2015;6(1):6413. doi:.
  91. Kaminski R, Chen Y, Fischer T, Tedaldi E, Napoli A, Zhang Y, et al. Elimination of HIV-1 genomes from human T-lymphoid cells by CRISPR/Cas9 gene editing. Sci Rep. 2016;6(1):22555. doi:.
  92. Lebbink RJ, de Jong DCM, Wolters F, Kruse EM, van Ham PM, Wiertz EJ, et al. A combinational CRISPR/Cas9 gene-editing approach can halt HIV replication and prevent viral escape. Sci Rep. 2017;7(1):41968. doi:.
  93. Cradick TJ, Keck K, Bradshaw S, Jamieson AC, McCaffrey AP. Zinc-finger nucleases as a novel therapeutic strategy for targeting hepatitis B virus DNAs. Mol Ther. 2010;18(5):947–54. doi:.
  94. Bloom K, Ely A, Mussolino C, Cathomen T, Arbuthnot P. Inactivation of hepatitis B virus replication in cultured cells and in vivo with engineered transcription activator-like effector nucleases. Mol Ther. 2013;21(10):1889–97. doi:.
  95. Lin SR, Yang HC, Kuo YT, Liu CJ, Yang TY, Sung KC, et al. The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo. Mol Ther Nucleic Acids. 2014;3:e186. doi:.
  96. Kennedy EM, Bassit LC, Mueller H, Kornepati AVR, Bogerd HP, Nie T, et al. Suppression of hepatitis B virus DNA accumulation in chronically infected cells using a bacterial CRISPR/Cas RNA-guided DNA endonuclease. Virology. 2015;476:196–205. doi:.
  97. Seeger C, Sohn JA. Targeting hepatitis B virus with CRISPR/Cas9. Mol Ther Nucleic Acids. 2014;3:e216. doi:.
  98. Rupp LJ, Schumann K, Roybal KT, Gate RE, Ye CJ, Lim WA, et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep. 2017;7(1):737. doi:.
  99. Klebanoff CA, Rosenberg SA, Restifo NP. Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med. 2016;22(1):26–36. doi:.
  100. Zhang Z, Zhang Y, Gao F, Han S, Cheah KS, Tse HF, et al. CRISPR/Cas9 genome-editing system in human stem cells: Current status and future prospects. Mol Ther Nucleic Acids. 2017;9:230–41. doi:.
  101. Avior Y, Lezmi E, Yanuka D, Benvenisty N. Modeling developmental and tumorigenic aspects of trilateral retinoblastoma via human embryonic stem cells. Stem Cell Reports. 2017;8(5):1354–65. doi:.
  102. Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun. 2015;6(1):8715. doi:.
  103. Wu Y, Liang D, Wang Y, Bai M, Tang W, Bao S, et al. Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell Stem Cell. 2013;13(6):659–62. doi:.
  104. Xie F, Ye L, Chang JC, Beyer AI, Wang J, Muench MO, et al. Seamless gene correction of β-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac. Genome Res. 2014;24(9):1526–33. doi:.
  105. Li HL, Fujimoto N, Sasakawa N, Shirai S, Ohkame T, Sakuma T, et al. Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Reports. 2015;4(1):143–54. doi:.
  106. Xu X, Tay Y, Sim B, Yoon SI, Huang Y, Ooi J, et al. Reversal of phenotypic abnormalities by CRISPR/Cas9-mediated gene correction in Huntington disease patient-derived induced pluripotent stem cells. Stem Cell Reports. 2017;8(3):619–33. doi:.
  107. Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med. 2018;378(14):1323–34. doi:.
  108. Hawkins RD, Hon GC, Lee LK, Ngo Q, Lister R, Pelizzola M, et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. 2010;6(5):479–91. doi:.
  109. Wen B, Wu H, Shinkai Y, Irizarry RA, Feinberg AP. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat Genet. 2009;41(2):246–50. doi:.
  110. Lupiáñez DG, Kraft K, Heinrich V, Krawitz P, Brancati F, Klopocki E, et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell. 2015;161(5):1012–25. doi:.
  111. Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet. 2014;15(6):423–37. doi:.
  112. Ip JPK, Mellios N, Sur M. Rett syndrome: insights into genetic, molecular and circuit mechanisms. Nat Rev Neurosci. 2018;19(6):368–82. doi:.
  113. Maierhofer A, Flunkert J, Oshima J, Martin GM, Haaf T, Horvath S. Accelerated epigenetic aging in Werner syndrome. Aging (Albany NY). 2017;9(4):1143–52. doi:.
  114. Colak D, Zaninovic N, Cohen MS, Rosenwaks Z, Yang WY, Gerhardt J, et al. Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science. 2014;343(6174):1002–5. doi:.
  115. Angulo MA, Butler MG, Cataletto ME. Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. J Endocrinol Invest. 2015;38(12):1249–63. doi:.
  116. Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci. 2011;34(6):293–303. doi:.
  117. Feng Y, Jankovic J, Wu YC. Epigenetic mechanisms in Parkinson’s disease. J Neurol Sci. 2015;349(1-2):3–9. doi:.
  118. De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, et al. Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014;17(9):1156–63. doi:.
  119. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59. doi:.
  120. Garcia-Bloj B, Moses C, Sgro A, Plani-Lam J, Arooj M, Duffy C, et al. Waking up dormant tumor suppressor genes with zinc fingers, TALEs and the CRISPR/dCas9 system. Oncotarget. 2016;7(37):60535–54. doi:.
  121. Choudhury SR, Cui Y, Lubecka K, Stefanska B, Irudayaraj J. CRISPR-dCas9 mediated TET1 targeting for selective DNA demethylation at BRCA1 promoter. Oncotarget. 2016;7(29):46545–56. doi:.
  122. Moreno AM, Fu X, Zhu J, Katrekar D, Shih YV, Marlett J, et al. In situ gene therapy via AAV-CRISPR-Cas9-mediated targeted gene regulation. Mol Ther. 2018;26(7):1818–27. doi:.