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Molecular Biotechnology

, Volume 55, Issue 1, pp 54–62 | Cite as

Biological and Biomedical Applications of Engineered Nucleases

  • Yunzhi Pan
  • Li Xiao
  • Alice S. S. Li
  • Xu Zhang
  • Pierre Sirois
  • Jia ZhangEmail author
  • Kai LiEmail author
Reviews

Abstract

The development of engineered nucleases is the fruit of a new technological approach developed in the last two decades which has led to significant benefits on genome engineering, particularly on gene therapy. These applications enable efficient and specific genetic modifications via the induction of a double-strand break (DSB) in a specific genomic target sequence, followed by the homology-directed repair (HDR) or non-homologous end joining (NHEJ) pathways. In addition to the application on gene modification in cells and intact organisms, a number of recent papers have reported that this gene editing technology can be applied effectively to human diseases. With the promising data obtained using engineered endonucleases in gene therapy, it appears reasonable to expect that more diseases could be treated and even be cured in this new era of individualized medicine. This paper first brief introduces the development of engineered nucleases with a special emphasis on zinc-finger nucleases (ZFNs) and transcription activator-like effector (TALE) nucleases (TALENs), and then takes CCR5-based gene therapy as an example to discuss the therapeutic applications of engineered nucleases.

Keywords

Engineered nucleases ZFNs TALENs Gene therapy CCR5 HIV 

Notes

Acknowledgments

This study is partially supported by National Natural Science Foundation of China (No. 30970877), Chinese National 863 Major Grant (No. 2012AA020905), the Priority Academic Program Development of Jiangsu Higher Education Institutions and Innovation Project of Jiangsu Graduate Education (No. CXZZ11_0117).

References

  1. 1.
    He, N., Zeng, X., Wang, W., Deng, K., Pan, Y., Xiao, L., et al. (2011). Challenges and future expectations of reversed gene therapy. Nanoscience and Nanotechnology, 11, 8634–8638.CrossRefGoogle Scholar
  2. 2.
    Moscou, M. J., & Bogdanove, A. J. (2009). A simple cipher governs DNA recognition by TAL effectors. Science, 326, 1501.CrossRefGoogle Scholar
  3. 3.
    Boch, J., Scholze, H., Schornack, S., Landgraf, A., Hahn, S., Kay, S., et al. (2009). Breaking the code of DNA binding specificity of TAL-type III effectors. Science, 326, 1509–1512.CrossRefGoogle Scholar
  4. 4.
    Morbitzer, R., Römer, P., Boch, J., & Lahaye, T. (2011). Regulation of selected genome loci using de novo-engineered transcription activator-like effector (TALE)-type transcription factor. Proceedings of the National Academy of Sciences of the United States of America, 107, 21617–21622.CrossRefGoogle Scholar
  5. 5.
    Geissler, R., Scholze, H., Hahn, S., Streubel, J., Bonas, U., Behrens, S. E., et al. (2011). Transcriptional activators of human genes with programmable DNA-specificity. PLoS ONE, 6, e19509.CrossRefGoogle Scholar
  6. 6.
    Christian, M., Cermak, T., Doyle, E. L., Schmidt, C., Zhang, F., Hummel, A., et al. (2010). TAL effector nucleases create targeted DNA double-strand breaks. Genetics, 186, 757–761.CrossRefGoogle Scholar
  7. 7.
    Mahfouz, M. M., Li, L., Shamimuzzaman, M., Wibowo, A., Fang, X., & Zhu, J. K. (2011). De novo-engineered transcription activator-like effector (TALE) hybrid nuclease with novel DNA binding specificity creates double-strand breaks. Proceedings of the National Academy of Sciences of the United States of America, 108, 2623–2628.CrossRefGoogle Scholar
  8. 8.
    Beumer, K. J., Trautman, J. K., Bozas, A., Liu, J. L., Rutter, J., Gall, J. G., et al. (2008). Efficient gene targeting in drosophila by direct embryo injection with zinc-finger nucleases. Proceedings of the National Academy of Sciences of the United States of America, 105, 19821–19826.CrossRefGoogle Scholar
  9. 9.
    Doyon, Y., McCammon, J. M., Miller, J. C., Faraji, F., Ngo, C., Katibah, G. E., et al. (2008). Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleases. Nature Biotech, 26, 702–708.CrossRefGoogle Scholar
  10. 10.
    Meng, X., Noyes, M. B., Zhu, L. J., Lawson, N. D., & Wolfe, S. A. (2008). Targeted gene inactivation in zebrafish using engineered zinc-finger nucleases. Nature Biotech, 26, 695–701.CrossRefGoogle Scholar
  11. 11.
    Foley, J. E., Yeh, J. R., Maeder, M. L., Reyon, D., Sander, J. D., Peterson, R. T., et al. (2009). Rapid mutation of endogenous zebrafish genes using zinc finger nucleases made by Oligomerized Pool ENgineering (OPEN). PLoS ONE, 4, e4348.CrossRefGoogle Scholar
  12. 12.
    Siekmann, A. F., Standley, C., Fogarty, K. E., Wolfe, S. A., & Lawson, N. D. (2009). Chemokine signaling guides regional patterning of the first embryonic artery. Genes & Development, 23, 2272–2277.CrossRefGoogle Scholar
  13. 13.
    Santiago, Y., Chan, E., Liu, P. Q., Orlando, S., Zhang, L., Urnov, F. D., et al. (2008). Targeted gene knockout in mammalian cells using engineered zinc finger nucleases. Proceedings of the National Academy of Sciences of the United States of America, 105, 5809–5814.CrossRefGoogle Scholar
  14. 14.
    Cost, G. J., Freyvert, Y., Vafiadis, A., Santiago, Y., Miller, J. C., Rebar, E., et al. (2009). BAK and BAX deletion using zinc-finger nucleases yields apoptosis-resistant CHO cells. Biotechnology and Bioengineering, 105, 330–340.CrossRefGoogle Scholar
  15. 15.
    Liu, P. Q., Chan, E. M., Cost, G. J., Zhang, L., Wang, J., Miller, J. C., et al. (2010). Generation of a triple-gene knockout mammalian cell line using engineered zinc-finger nucleases. Biotechnology and Bioengineering, 106, 97–105.Google Scholar
  16. 16.
    Geurts, A. M., Cost, G. J., Freyvert, Y., Zeitler, B., Miller, J. C., Choi, V. M., et al. (2009). Knockout rats via embryo microinjection of zinc-finger nucleases. Science, 325, 433.CrossRefGoogle Scholar
  17. 17.
    Lee, H. J., Kim, E., & Kim, J. S. (2010). Targeted chromosomal deletions in human cells using zinc finger nucleases. Genome Research, 20, 81–89.CrossRefGoogle Scholar
  18. 18.
    Miller, J. C., Tan, S., Qiao, G., Barlow, K. A., Wang, J., Xia, D. F., et al. (2011). A TALE nuclease architecture for efficient genome editing. Nature Biotechnology, 29, 143–148.CrossRefGoogle Scholar
  19. 19.
    Huang, P., Xiao, A., Zhou, M., Zhu, Z., Lin, S., & Zhang, B. (2011). Heritable gene targeting in zebrafish using customized TALENs. Nature Biotechnology, 29, 699–700.CrossRefGoogle Scholar
  20. 20.
    Silva, G., Poirot, L., Galetto, R., Smith, J., Montoya, G., Duchateau, P., et al. (2011). Meganucleases and other tools for targeted genome engineering: perspectives and challenges for gene therapy. Current Gene Therapy, 11, 11–27.CrossRefGoogle Scholar
  21. 21.
    Cai, C. Q., Doyon, Y., Ainley, W. M., Miller, J. C., Dekelver, R. C., Moehle, E. A., et al. (2009). Targeted transgene integration in plant cells using designed zinc finger nucleases. Plant Molecular Biology, 69, 699–709.CrossRefGoogle Scholar
  22. 22.
    Shukla, V. K., Doyon, Y., Miller, J. C., DeKelver, R. C., Moehle, E. A., Worden, S. E., et al. (2009). Precise genome modification in the crop species Zea mays using zinc-finger nucleases. Nature, 459, 437–441.CrossRefGoogle Scholar
  23. 23.
    Goldberg, A. D., Banaszynski, L. A., Noh, K. M., Lewis, P. W., Elsaesser, S. J., Stadler, S., et al. (2010). Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell, 140, 678–691.CrossRefGoogle Scholar
  24. 24.
    Moehle, E. A., Rock, J. M., Lee, Y. L., Jouvenot, Y., DeKelver, R. C., Gregory, P. D., et al. (2007). Targeted gene addition into a specified location in the human genome using designed zinc finger nucleases. Proceedings of the National Academy of Sciences of the United States of America, 104, 3055–3060.CrossRefGoogle Scholar
  25. 25.
    Lombardo, A., Genovese, P., Beausejour, C. M., Colleoni, S., Lee, Y. L., Kim, K. A., et al. (2007). Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nature Biotech, 25, 1298–1306.CrossRefGoogle Scholar
  26. 26.
    Benabdallah, B. F., Allard, E., Yao, S., Friedman, G., Gregory, P. D., Eliopoulos, N., et al. (2010). Targeted gene addition to human mesenchymal stromal cells as a cell-based plasma-soluble protein delivery platform. Cytotherapy, 12, 394–399.CrossRefGoogle Scholar
  27. 27.
    Hockemeyer, D., Soldner, F., Beard, C., Gao, Q., Mitalipova, M., DeKelver, R. C., et al. (2009). Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nature Biotechnology, 27, 851–857.CrossRefGoogle Scholar
  28. 28.
    Hockemeyer, D., Wang, H., Kiani, S., Lai, C. S., Gao, Q., Cassady, J. P., et al. (2011). Genetic engineering of human pluripotent cells using TALE nucleases. Nature Biotechnology, 29, 731–734.CrossRefGoogle Scholar
  29. 29.
    Urnov, F. D., Miller, J. C., Lee, Y. L., Beausejour, C. M., Rock, J. M., Augustus, S., et al. (2005). Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature, 435, 646–651.CrossRefGoogle Scholar
  30. 30.
    Maeder, M. L., Thibodeau-Beganny, S., Osiak, A., Wright, D. A., Anthony, R. M., Eichtinger, M., et al. (2008). Rapid ‘open-source’ engineering of customized zinc-finger nucleases for highly efficient gene modification. Molecular Cell, 31, 294–301.CrossRefGoogle Scholar
  31. 31.
    Li, H., Haurigot, V., Doyon, Y., Li, T., Wong, S. Y., Bhagwat, A. S., et al. (2011). In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature, 475, 217–221.CrossRefGoogle Scholar
  32. 32.
    Townsend, J. A., Wright, D. A., Winfrey, R. J., Fu, F., Maeder, M. L., Joung, J. K., et al. (2009). High-frequency modification of plant genes using engineered zinc-finger nucleases. Nature, 459, 442–445.CrossRefGoogle Scholar
  33. 33.
    Osakabe, K., Osakabe, Y., & Toki, S. (2010). Site-directed mutagenesis in Arabidopsis using custom-designed zinc finger nucleases. Proceedings of the National Academy of Sciences of the United States of America, 107, 12034–12039.CrossRefGoogle Scholar
  34. 34.
    Goldberg, A. D., Banaszynski, L. A., Noh, K. M., Lewis, P. W., Elsaesser, S. J., Stadler, S., et al. (2011). Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell, 140, 678–691.CrossRefGoogle Scholar
  35. 35.
    Caroll, D., & Zhang, B. (2011). Primer and interviews: Advances in targeted gene modification. Developmental Dynamics, 240, 2688–2696.CrossRefGoogle Scholar
  36. 36.
    Lee, H. J., Kweon, J., Kim, E., Kim, S., & Kim, J. S. (2012). Targeted chromosomal duplications and inversions in the human genome using zinc finger nucleases. Genome Research, 22, 539–548.CrossRefGoogle Scholar
  37. 37.
    Chen, L. L., Zhang, J., Gao, H. L., Liao, D. F., Li, K., (2005) The relationship between CCR5 and HIV-1 disease. Journal of University of South China (Medical Edition) 33, 166–170 (In Chinese).Google Scholar
  38. 38.
    Zaitseva, M., Blauvelt, A., Lee, S., Lapham, C. K., Klaus-Kovtun, V., Mostowski, H., et al. (1997). Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: Implications for HIV primary infection. Nature Medicine, 3, 1369–1375.CrossRefGoogle Scholar
  39. 39.
    Lopalco, L., Barassi, C., Pastori, C., Longhi, R., Burastero, S. E., Tambussi, G., et al. (2000). CCR5-reactive antibodies in seronegative partners of HIV-seropositive individuals down-modulate surface CCR5 in vivo and neutralize the infectivity of R5 strains of HIV-1 in vitro. Journal of Immunology, 164, 3426–3433.Google Scholar
  40. 40.
    Perez, E. E., Wang, J., Miller, J. C., Jouvenot, Y., Kim, K. A., Liu, O., et al. (2008). Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nature Biotechnology, 26, 808–816.CrossRefGoogle Scholar
  41. 41.
    Holt, N., Wang, J., Kim, K., Friedman, G., Wang, X., Taupin, V., et al. (2010). Human hematopoietic stem/progenitor cells modified by zinc-finger nuclease targeted to CCR5 control HIV-1 in vivo. Nature Biotechnology, 28, 839–847.CrossRefGoogle Scholar
  42. 42.
    Mussolino, C., Morbitzer, R., Lütge, F., Dannemann, N., Lahaye, T., Cathomen, T., et al. (2011). A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Research, 39, 9283–9293.CrossRefGoogle Scholar
  43. 43.
    Allers, K., Hütter, G., Hofmann, J., Loddenkemper, C., Rieger, K., Thiel, E., et al. (2011). Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood, 117, 2791–2799.CrossRefGoogle Scholar
  44. 44.
    Li, K., Zhang, J., Xiao, L., & Sirois, Pierre. (2011). Gene therapy: Hope for HIV infection cure. Blood, e-letter, 01, 26.Google Scholar
  45. 45.
    He, N., Zeng, X., Wang, W., Deng, K. L., Pan, Y., Xiao, L., et al. (2011). Challenges and future expectations of reversed gene therapy. Journal of Nanoscience and Nanotechnology, 11, 8634–8638.CrossRefGoogle Scholar
  46. 46.
    Zhang, J., Li, A. S. S., Kou, X., Xiao, L., Li, P., He, N., et al. (2012). Why CCR5 is chosen as the target for stem cell gene therapy for HIV infection? Journal of Nanoscience and Nanotechnology, 12, 2045–2048.CrossRefGoogle Scholar
  47. 47.
    Bibikova, M., Beumer, K., Trautman, J. K., & Carroll, D. (2003). Enhancing gene targeting with designed zinc finger nucleases. Science, 300, 764.CrossRefGoogle Scholar
  48. 48.
    Beumer, K., Bhattacharyya, G., Bibikova, M., Trautman, J. K., & Carroll, D. (2006). Efficient gene targeting in Drosophila with zinc-finger nucleases. Genetics, 172, 2391–2403.CrossRefGoogle Scholar
  49. 49.
    Malphettes, L., Freyvert, Y., Chang, J., Liu, P. Q., Chan, E., Miller, J. C., et al. (2010). Highly efficient deletion of FUT8 in CHO cell lines using zinc-finger nucleases yields cells that produce completely nonfucosylated antibodies. Biotechnology and Bioengineering, 106, 774–783.CrossRefGoogle Scholar
  50. 50.
    Mashimo, T., Takizawa, A., Voigt, B., Yoshimi, K., Hiai, H., Kuramoto, T., et al. (2010). Generation of knockout rats with X-linked severe combined immunodeficiency (X-SCID) using zinc-finger nucleases. PLoS ONE, 5, e8870.CrossRefGoogle Scholar
  51. 51.
    Del Prete, G. Q., Haggarty, B., Leslie, G. J., Jordan, A. P., Romano, J., Wang, N., et al. (2009). Derivation and characterization of a simian immunodeficiency virus SIVmac239 variant with tropism for CXCR4. Journal of Virology, 83, 9911–9922.CrossRefGoogle Scholar
  52. 52.
    Doyon, Y., Choi, V. M., Xia, D. F., Vo, T. D., Gregory, P. D., & Holmes, M. C. (2010). A transient cold shock enhances zinc-finger nuclease-mediated gene disruption. Nature Methods, 7, 459–460.CrossRefGoogle Scholar
  53. 53.
    Zhang, F., Maeder, M. L., Unger-Wallace, E., Hoshaw, J. P., Reyon, D., Christian, M., et al. (2010). High frequency targeted mutagenesis in Arabidopsis thaliana using zinc finger nuclease. Proc. Proc Natl Acad Sci USA, 107, 12028–12033.CrossRefGoogle Scholar
  54. 54.
    Zou, J., Maeder, M. L., Mali, P., Pruett-Miller, S. M., Thibodeau-Beganny, S., Chou, B. K., et al. (2009). Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell, 5, 97–110.CrossRefGoogle Scholar
  55. 55.
    Zhang, F., Cong, L., Lodato, S., Kosuri, S., Church, G. M., & Arlotta, P. (2011). Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription. Nature Biotechnology, 29, 149–153.CrossRefGoogle Scholar
  56. 56.
    Wood, A. J., Lo, T. W., Zeitler, B., Pickle, C. S., Ralston, E. J., Lee, A. H., et al. (2011). Targeted genome editing across species using ZFNs and TALENs. Science, 333, 307.CrossRefGoogle Scholar
  57. 57.
    Tesson, L., Usal, C., Ménoret, S., Leung, E., Niles, B. J., Remy, S., et al. (2011). Knockout rats generated by embryo microinjection of TALENs. Nature Biotechnology, 29, 695–696.CrossRefGoogle Scholar
  58. 58.
    Thermes, V., Grabher, C., Ristoratore, F., Bourrat, F., Choulika, A., Wittbrodt, J., et al. (2002). I-SceI meganuclease mediates highly efficient transgenesis in fish. Mechanisms of Development, 118, 91–98.CrossRefGoogle Scholar
  59. 59.
    Grabher, C., & Wittbrodt, J. (2007). Meganuclease and transposon mediated transgenesis in medaka. Genome Biology, 8, S10.CrossRefGoogle Scholar
  60. 60.
    Grosse, S., Huot, N., Mahiet, C., Arnould, S., Barradeau, S., Clerre, D. L., et al. (2011). Meganuclease-mediated inhibition of HSV1 infection in cultured cells. Molecular Therapy, 19, 694–702.CrossRefGoogle Scholar
  61. 61.
    Kim, H. J., Lee, H. J., Kim, H., Cho, S. W., & Kim, J. S. (2009). Targeted genome editing in human cells with zinc finger nucleases constructed via modular assembly. Genome Research, 19, 1279–1288.CrossRefGoogle Scholar
  62. 62.
    Kim, H., Um, E., Cho, S. R., Jung, C., Kim, H., & Kim, J. S. (2011). Surrogate reporters for enrichment of cells with nuclease-induced mutations. Nature Methods, 8, 941–943.CrossRefGoogle Scholar
  63. 63.
    Kim, S., Lee, M. J., Kim, H., Kang, M., & Kim, J. S. (2011). Preassembled zinc-finger arrays for rapid construction of ZFNs. Nature Methods, 8, 7.CrossRefGoogle Scholar
  64. 64.
    Sun, N., Liang, J., Abil, Z., & Zhao, H. (2012). Optimized TAL effector nucleases (TALENs) for use in treatment of sickle cell disease. Molecular BioSystems, 8, 1255–1263.CrossRefGoogle Scholar
  65. 65.
    Bonas, U., Stall, R. E., & Stskawicz, B. J. (1989). Genetic and structural characterization of the avirulence gene avrBs3 from Xanthomonas campestris pv. campesris. Molecular and General Genetics, 218(1), 127–136.CrossRefGoogle Scholar
  66. 66.
    Miller, J., McLachlan, A. D., & Klug, A. (1985). Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes. EMBO Journal, 4, 1609–1614.Google Scholar
  67. 67.
    Kim, Y. G., Cha, J., & Chandrasegaran, S. (1996). Hybrid restriction enzymes: Zinc finger fusions to FokI cleavage domain. Proceedings of the National Academy of Sciences of the USA, 93, 1156–1160.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Molecular Diagnostics and Biopharmaceutics, College of Pharmaceutical ScienceSoochow UniversitySuzhouChina
  2. 2.University of WaterlooOntarioCanada
  3. 3.Genotheramics Corp.San DiegoUSA
  4. 4.CHUL Research CenterLaval UniversityQuebecCanada

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