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Gene Editing in Human Pluripotent Stem Cells: Recent Advances for Clinical Therapies

  • Hatice Burcu Şişli
  • Taha Bartu Hayal
  • Selin Seçkin
  • Selinay Şenkal
  • Binnur Kıratlı
  • Fikrettin Şahin
  • Ayşegül DoğanEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series

Abstract

The identification of human embryonic stem cells and reprogramming technology to obtain induced pluripotent stem cells from adult somatic cells have provided unique opportunity to create human disease models, gene editing strategies and cell therapy options.

Development of pluripotent stem cells from somatic cells and genomic manipulation tools enabled to use site specific nucleases in the cell therapy research. Identification of efficient gene manipulation, safe differentiation and use will provide a novel strategy to treat many diseases in the near future. Current available registered clinical trials clearly indicate the need for pluripotent stem cell and gene therapy treatment options. Although gene editing based pluripotent stem cell research is a popular field for research worldwide, improvement of clinical approaches for treatment still remains to be investigated. In this review, we summarized the current situation of gene editing based pluripotent cell therapy developments and applications in clinics.

Keywords

Cell therapy Clinical trial Gene therapy Pluripotent stem cell Regenerative medicine 

Abbreviations

AAV

Adeno-associated virus

AAVS1

AAV integration site 1

Cas9

CRISPR-associated system

CCR5

CC chemokine receptor 5

CD4

Cluster of differentiation 4

CMV

Cytomegalovirus

CRISPR

Clustered regularly interspaced short palindromic repeat

CRX

Cone-rod homeobox

DNA

Deoxyribonucleic acid

DSB

Double-strand break

ESC

Embryonic stem cell

FIH

First-In-Human

GBA

Glucosylceramidase Beta

GCase

Glucocerebrosidase

GFP

Green fluorescent protein

HDR

Homology-directed repair

hES

Human embryonic stem

hESC

Human ESC

HIV

Human immunodeficiency virus

HPV

Human papillomavirus

HR

Homologous recombination

HSC

Hematopoietic stem cell

iPS

Induced pluripotent stem

iPSC

Induced pluripotent stem cell

MELAS

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

MiPSC

Mitochondrial disease patient-specific induced pluripotent stem cell

mtDNA

Mitochondrial DNA

MTS

Mitochondrial targeting sequence

NHEJ

Non-homologous end-joining

PITX3

Pituitary homeobox 3

PSC

Pluripotent stem cell

RNA

Ribonucleic acid

RPE

Retinal pigment epithelium

sgRNA

Single guide RNA

SHANK3

SH3 and multiple ankyrin repeat domains 3

SSN

Site-specific nuclease

TALE

Tal effector protein

TALEN

Transcription activator-like effector nuclease

ZF

Zinc finger

ZFN

Zinc-finger nuclease

References

  1. Barrangou R, Horvath P (2017) A decade of discovery: CRISPR functions and applications. Nat Microbiol 2:17092Google Scholar
  2. Bengtsson NE, Hall JK, Odom GL, Phelps MP, Andrus CR, Hawkins RD et al (2017) Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for duchenne muscular dystrophy. Nat Commun 8:14454Google Scholar
  3. Boch J (2011) Tales of genome targeting. Nat Biotechnol 29(2):135–136Google Scholar
  4. Boch J, Bonas U (2010) Xanthomonas AvrBs3 family-type III effectors: discovery and function. Annu Rev Phytopathol 48:419–436Google Scholar
  5. Carroll D (2011) Genome engineering with zinc-finger nucleases. Genetics 188(4):773–782Google Scholar
  6. Chandrasekaran AP, Song M, Ramakrishna S (2017) Genome editing: a robust technology for human stem cells. Cell Mol Life Sci 74(18):3335–3346Google Scholar
  7. Chang CW, Lai YS, Westin E, Khodadadi-Jamayran A, Pawlik KM, Lamb LS Jr et al (2015) Modeling human severe combined immunodeficiency and correction by CRISPR/Cas9-enhanced gene targeting. Cell Rep 12(10):1668–1677Google Scholar
  8. Chang CY, Ting HC, Su HL, Jeng JR (2018) Combining induced pluripotent stem cells and genome editing technologies for clinical applications. Cell Transplant 27(3):379–392Google Scholar
  9. Collin J, Mellough CB, Dorgau B, Przyborski S, Moreno-Gimeno I, Lako M (2016) Using zinc finger nuclease technology to generate CRX-reporter human embryonic stem cells as a tool to identify and study the emergence of photoreceptors precursors during pluripotent stem cell differentiation. Stem Cells 34(2):311–321Google Scholar
  10. Cubbon A, Ivancic-Bace I, Bolt EL (2018) CRISPR-Cas immunity, DNA repair and genome stability. Biosci Rep 38(5):BSR20180457Google Scholar
  11. Dambournet D, Sochacki KA, Cheng AT, Akamatsu M, Taraska JW, Hockemeyer D et al (2018) Genome-edited human stem cells expressing fluorescently labeled endocytic markers allow quantitative analysis of clathrin-mediated endocytosis during differentiation. J Cell Biol 217(9):3301–3311Google Scholar
  12. Doppler SA, Deutsch MA, Lange R, Krane M (2013) Cardiac regeneration: current therapies-future concepts. J Thorac Dis 5(5):683–697Google Scholar
  13. Doss MX, Sachinidis A (2019) Current challenges of iPSC-based disease modeling and therapeutic implications. Cell 8(5):pii: E403Google Scholar
  14. Doudna JA, Charpentier E (2014) Genome editing. The new frontier of genome engineering with CRISPR-CAS9. Science 346(6213):1258096Google Scholar
  15. Firth AL, Menon T, Parker GS, Qualls SJ, Lewis BM, Ke E et al (2015) Functional gene correction for cystic fibrosis in lung epithelial cells generated from patient iPSCs. Cell Rep 12(9):1385–1390Google Scholar
  16. Folger KR, Wong EA, Wahl G, Capecchi MR (1982) Patterns of integration of DNA microinjected into cultured mammalian cells: evidence for homologous recombination between injected plasmid DNA molecules. Mol Cell Biol 2(11):1372–1387Google Scholar
  17. Gaspar V, De Melo-Diogo D, Costa E, Moreira A, Queiroz J, Pichon C et al (2015) Minicircle DNA vectors for gene therapy: advances and applications. Expert Opin Biol Ther 15(3):353–379Google Scholar
  18. Ginn SL, Amaya AK, Alexander IE, Edelstein M, Abedi MR (2018) Gene therapy clinical trials worldwide to 2017: an update. J Gene Med 20(5):E3015Google Scholar
  19. Gundner AL, Meyer CA, Aigner S, Christensen K, Patsch C, Jagasia R et al (2017) Generation of a homozygous GBA deletion human embryonic stem cell line. Stem Cell Res 23:122–126Google Scholar
  20. Hamed MY, Arya G (2016) Zinc finger protein binding to DNA: an energy perspective using molecular dynamics simulation and free energy calculations on mutants of both zinc finger domains and their specific DNA bases. J Biomol Struct Dyn 34(5):919–934Google Scholar
  21. Hartley BJ, Fabb SA, Finnin BA, Haynes JM, Pouton CW (2014) Zinc-finger nuclease enhanced gene targeting in human embryonic stem cells. J Vis Exp 90(51764):1–7Google Scholar
  22. Hendriks WT, Warren CR, Cowan CA (2016) Genome editing in human pluripotent stem cells: approaches, pitfalls, and solutions. Cell Stem Cell 18(1):53–65Google Scholar
  23. Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M, Dekelver RC et al (2009) Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol 27(9):851–857Google Scholar
  24. Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP et al (2011) Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol 29(8):731–734Google Scholar
  25. Hotta A, Yamanaka S (2015) From genomics to gene therapy: induced pluripotent stem cells meet genome editing. Annu Rev Genet 49:47–70Google Scholar
  26. Hou XH, Guo XY, Chen Y, He CY, Chen ZY (2015) Increasing the minicircle DNA purity using an enhanced triplex DNA technology to eliminate DNA contaminants. Mol Ther Methods Clin Dev 1:14062Google Scholar
  27. Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157(6):1262–1278Google Scholar
  28. Jia F, Wilson KD, Sun N, Gupta DM, Huang M, Li Z et al (2010) A nonviral minicircle vector for deriving human iPS cells. Nat Methods 7(3):197–199Google Scholar
  29. Kathuria A, Nowosiad P, Jagasia R, Aigner S, Taylor RD, Andreae LC et al (2018) Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development. Mol Psychiatry 23(3):735–746Google Scholar
  30. Khan IF, Hirata RK, Wang PR, Li Y, Kho J, Nelson A et al (2010) Engineering of human pluripotent stem cells by AAV-mediated gene targeting. Mol Ther 18(6):1192–1199Google Scholar
  31. Kimbrel EA, Lanza R (2015) Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov 14(10):681–692Google Scholar
  32. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR (2016) Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533(7603):420–424Google Scholar
  33. Li C, Ding L, Sun CW, Wu LC, Zhou D, Pawlik KM et al (2016) Novel HDAd/EBV reprogramming vector and highly efficient Ad/CRISPR-Cas sickle cell disease gene correction. Sci Rep 6:30422Google Scholar
  34. Li YH, Yu CY, Li XX, Zhang P, Tang J, Yang Q et al (2018) Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics. Nucleic Acids Res 46(D1):D1121–D11D7Google Scholar
  35. Liu T, Wang Y, Tai G, Zhang S (2009) Could co-transplantation of iPS cells derived hepatocytes and MSCs cure end-stage liver disease? Cell Biol Int 33(11):1180–1183Google Scholar
  36. Liu Y, Liu H, Sauvey C, Yao L, Zarnowska ED, Zhang SC (2013) Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat Protoc 8(9):1670–1679Google Scholar
  37. Mahata B, Biswas K (2017) Generation of stable knockout mammalian cells by TALEN-mediated locus-specific gene editing. Methods Mol Biol 1498:107–120Google Scholar
  38. Marraffini LA, Sontheimer EJ (2010) CRISPR interference: RNA-directed adaptive immunity in bacteria and archaea. Nat Rev Genet 11(3):181–190Google Scholar
  39. Miller JC, Holmes MC, Wang J, Guschin DY, Lee YL, Rupniewski I et al (2007) An improved zinc-finger nuclease architecture for highly specific genome editing. Nat Biotechnol 25(7):778–785Google Scholar
  40. Munye MM, Tagalakis AD, Barnes JL, Brown RE, Mcanulty RJ, Howe SJ et al (2016) Minicircle dna provides enhanced and prolonged transgene expression following airway gene transfer. Sci Rep 6:23125Google Scholar
  41. Mussolino C, Morbitzer R, Lutge F, Dannemann N, Lahaye T, Cathomen T (2011) A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Res 39(21):9283–9293Google Scholar
  42. Park C, Kim DH, Son JS, Sung JJ, Lee J, Bae S et al (2015) Functional correction of large factor VIII gene chromosomal inversions in Hemophilia A patient-derived iPSCs using CRISPR-Cas9. Cell Stem Cell 17(2):213–220Google Scholar
  43. Perez-Pinera P, Ousterout DG, Gersbach CA (2012) Advances in targeted genome editing. Curr Opin Chem Biol 16(3–4):268–277Google Scholar
  44. Pingoud A, Jeltsch A (2001) Structure and function of type II restriction endonucleases. Nucleic Acids Res 29(18):3705–3727Google Scholar
  45. Ramamoorth M, Narvekar A (2015) Non viral vectors in gene therapy- an overview. J Clin Diagn Res 9(1):Ge01–Ge06Google Scholar
  46. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-CAS9 system. Nat Protoc 8(11):2281–2308Google Scholar
  47. Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R et al (1990) Gene transfer into humans — immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 323(9):570–578Google Scholar
  48. Sakuma T, Hosoi S, Woltjen K, Suzuki K, Kashiwagi K, Wada H et al (2013) Efficient TALEN construction and evaluation methods for human cell and animal applications. Genes Cells 18(4):315–326Google Scholar
  49. Sander JD, Joung JK (2014) CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 32(4):347–355Google Scholar
  50. Sander JD, Cade L, Khayter C, Reyon D, Peterson RT, Joung JK et al (2011) Targeted gene disruption in somatic zebrafish cells using engineered TALENs. Nat Biotechnol 29(8):697–698Google Scholar
  51. Shi Y, Inoue H, Wu JC, Yamanaka S (2017) Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 16(2):115–130Google Scholar
  52. Shimberg GD, Pritts JD, Michel SLJ (2018) Chapter 4: Iron–sulfur clusters in zinc finger proteins. In: David SS (ed) Methods in enzymology, vol 599. Academic, Cambridge, MA, USA pp 101–137Google Scholar
  53. Singh AM, Adjan Steffey VV, Yeshi T, Allison DW (2015) Gene editing in human pluripotent stem cells: choosing the correct path. J Stem Cell Regen Biol 1(1):1–5Google Scholar
  54. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676Google Scholar
  55. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872Google Scholar
  56. Takashima K, Inoue Y, Tashiro S, Muto K (2018) Lessons for reviewing clinical trials using induced pluripotent stem cells: examining the case of a first-in-human trial for age-related macular degeneration. Regen Med 13(2):123–128Google Scholar
  57. Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G et al (2014) Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370(10):901–910Google Scholar
  58. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147Google Scholar
  59. Tiyaboonchai A, Mac H, Shamsedeen R, Mills JA, Kishore S, French DL et al (2014) Utilization of the AAVS1 safe harbor locus for hematopoietic specific transgene expression and gene knockdown in human ES cells. Stem Cell Res 12(3):630–637Google Scholar
  60. Tran T, Doucoure H, Hutin M, Jaimes Nino LM, Szurek B, Cunnac S et al (2018) Efficient enrichment cloning of TAL effector genes from xanthomonas. Methods 5:1027–1032Google Scholar
  61. Trounson A, Dewitt ND (2016) Pluripotent stem cells progressing to the clinic. Nat Rev Mol Cell Biol 17(3):194–200Google Scholar
  62. Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD (2010) Genome editing with engineered zinc finger nucleases. Nat Rev Genet 11(9):636–646Google Scholar
  63. Wold WS, Toth K (2013) Adenovirus vectors for gene therapy, vaccination and cancer gene therapy. Curr Gene Ther 13(6):421–433Google Scholar
  64. Wolfs E, Holvoet B, Ordovas L, Breuls N, Helsen N, Schonberger M et al (2017) Molecular imaging of human embryonic stem cells stably expressing human PET reporter genes after zinc finger nuclease-mediated genome editing. J Nucl Med 58(10):1659–1665Google Scholar
  65. Wolinsky H (2009) The Pendulum Swung. President Barack Obama removes restrictions on stem-cell research, but are expectations now too high? EMBO Rep 10(5):436–439Google Scholar
  66. Wood AJ, Lo TW, Zeitler B, Pickle CS, Ralston EJ, Lee AH et al (2011) Targeted genome editing across species using ZFNs and TALENs. Science 333(6040):307Google Scholar
  67. Yahata N, Matsumoto Y, Omi M, Yamamoto N, Hata R (2017) TALEN-mediated shift of mitochondrial DNA heteroplasmy in MELAS-iPSCs with m.13513G>A mutation. Sci Rep 7(1):15557Google Scholar
  68. Yanagida A, Ito K, Chikada H, Nakauchi H, Kamiya A (2013) An in vitro expansion system for generation of human iPS cell-derived hepatic progenitor-like cells exhibiting a bipotent differentiation potential. PLoS One 8(7):E67541Google Scholar
  69. Yang Y, Wu H, Kang X, Liang Y, Lan T, Li T et al (2018) Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs. Protein Cell 9(3):283–297Google Scholar
  70. Zou J, Maeder ML, Mali P, Pruett-Miller SM, Thibodeau-Beganny S, Chou BK et al (2009) Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell 5(1):97–110Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Hatice Burcu Şişli
    • 1
  • Taha Bartu Hayal
    • 1
  • Selin Seçkin
    • 1
  • Selinay Şenkal
    • 1
  • Binnur Kıratlı
    • 1
  • Fikrettin Şahin
    • 1
  • Ayşegül Doğan
    • 1
    Email author
  1. 1.Department of Genetics and Bioengineering, Faculty of EngineeringYeditepe UniversityIstanbulTurkey

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