Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Refining strategies to translate genome editing to the clinic

Nature Medicine volume 23, pages 415–423 (2017)Cite this article

Subjects

Abstract

Recent progress in developing programmable nucleases, such as zinc-finger nucleases, transcription activator–like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)–Cas nucleases, have paved the way for gene editing to enter clinical practice. This translation is a result of combining high nuclease activity with high specificity and successfully applying this technology in various preclinical disease models, including infectious disease, primary immunodeficiencies, hemoglobinopathies, hemophilia and muscular dystrophy. Several clinical gene-editing trials, both ex vivo and in vivo, have been initiated in the past 2 years, including studies that aim to knockout genes as well as to add therapeutic transgenes. Here we discuss the advances made in the gene-editing field in recent years, and specify priorities that need to be addressed to expand therapeutic genome editing to further disease entities.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Designer-nuclease-induced genome editing.
Figure 2: Improving the specificity of engineered nucleases.
Figure 3: Production of an off-the-shelf CAR T cell product.
Figure 4: Roadmap: translating targeted genome editing into the clinic.

Similar content being viewed by others

References

  1. Gasiunas, G., Barrangou, R., Horvath, P. & Siksnys, V. Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc. Natl. Acad. Sci. USA 109, E2579–E2586 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cox, D.B., Platt, R.J. & Zhang, F. Therapeutic genome editing: prospects and challenges. Nat. Med. 21, 121–131 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Marketsandmarkets.comGenome Editing/Genome Engineering Market by Technology (CRISPR, TALEN, ZFN), Applications (Cell Line Engineering, Animal Genetic Engineering, Plant Genetic Engineering), End User (Biotechnology & Pharmaceutical Companies, CROs)—Global Forecast to 2021 (marketsandmarkets.com, 2016).

  5. Carroll, D. Genome engineering with zinc-finger nucleases. Genetics 188, 773–782 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Joung, J.K. & Sander, J.D. TALENs: a widely applicable technology for targeted genome editing. Nat. Rev. Mol. Cell Biol. 14, 49–55 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Naldini, L. Gene therapy returns to centre stage. Nature 526, 351–360 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Capecchi, M.R. Altering the genome by homologous recombination. Science 244, 1288–1292 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Rouet, P., Smih, F. & Jasin, M. Expression of a site-specific endonuclease stimulates homologous recombination in mammalian cells. Proc. Natl. Acad. Sci. USA 91, 6064–6068 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Urnov, F.D. et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435, 646–651 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Hoban, M.D. et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood 125, 2597–2604 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Genovese, P. et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature 510, 235–240 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. De Ravin, S.S. et al. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat. Biotechnol. 34, 424–429 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hubbard, N. et al. Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome. Blood 127, 2513–2522 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Traxler, E.A. et al. A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med. 22, 987–990 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dever, D.P. et al. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sather, B.D. et al. Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template. Sci. Transl. Med. 7, 307ra156 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Poirot, L. et al. Multiplex genome-edited T cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res. 75, 3853–3864 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Qasim, W. et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 9, eaaj2013 (2017).

    Article  PubMed  Google Scholar 

  21. Hoban, M.D. et al. CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Mol. Ther. 24, 1561–1569 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chu, V.T. et al. Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat. Biotechnol. 33, 543–548 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Maruyama, T. et al. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat. Biotechnol. 33, 538–542 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yu, C. et al. Small molecules enhance CRISPR genome editing in pluripotent stem cells. Cell Stem Cell 16, 142–147 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Song, J. et al. RS-1 enhances CRISPR/Cas9- and TALEN-mediated knock-in efficiency. Nat. Commun. 7, 10548 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kaufmann, K.B., Büning, H., Galy, A., Schambach, A. & Grez, M. Gene therapy on the move. EMBO Mol. Med. 5, 1642–1661 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li, H. et al. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475, 217–221 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sharma, R. et al. In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood 126, 1777–1784 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Suzuki, K. et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature 540, 144–149 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pankowicz, F.P. et al. Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia. Nat. Commun. 7, 12642 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nelson, C.E. et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351, 403–407 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Tabebordbar, M. et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351, 407–411 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Long, C. et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351, 400–403 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. Williams, D.A. & Thrasher, A.J. Concise review: lessons learned from clinical trials of gene therapy in monogenic immunodeficiency diseases. Stem Cells Transl. Med. 3, 636–642 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Solinís, M.A., del Pozo-Rodríguez, A., Apaolaza, P.S. & Rodríguez-Gascón, A. Treatment of ocular disorders by gene therapy. Eur. J. Pharm. Biopharm. 95Pt B, 331–342 (2015).

    Article  CAS  Google Scholar 

  36. Ruiz de Garibay, A.P., Delgado, D., Del Pozo-Rodríguez, A., Solinís, M.A. & Gascón, A.R. Multicomponent nanoparticles as nonviral vectors for the treatment of Fabry disease by gene therapy. Drug Des. Devel. Ther. 6, 303–310 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yin, H. et al. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat. Biotechnol. 34, 328–333 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zuris, J.A. et al. Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat. Biotechnol. 33, 73–80 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hornung, V. & Latz, E. Intracellular DNA recognition. Nat. Rev. Immunol. 10, 123–130 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Wang, J. et al. Homology-driven genome editing in hematopoietic stem and progenitor cells using ZFN mRNA and AAV6 donors. Nat. Biotechnol. 33, 1256–1263 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Holkers, M. et al. Adenoviral vector DNA for accurate genome editing with engineered nucleases. Nat. Methods 11, 1051–1057 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Mock, U. et al. mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5. Nucleic Acids Res. 43, 5560–5571 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hendel, A. et al. Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat. Biotechnol. 33, 985–989 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hu, J.H., Davis, K.M. & Liu, D.R. Chemical biology approaches to genome editing: understanding, controlling, and delivering programmable nucleases. Cell Chem. Biol. 23, 57–73 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Kim, S., Kim, D., Cho, S.W., Kim, J. & Kim, J.S. Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Res. 24, 1012–1019 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yu, K.R., Natanson, H. & Dunbar, C.E. Gene editing of human hematopoietic stem and progenitor cells: promise and potential hurdles. Hum. Gene Ther. 27, 729–740 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Doyon, Y. et al. Enhancing zinc-finger-nuclease activity with improved obligate heterodimeric architectures. Nat. Methods 8, 74–79 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Söllü, C. et al. Autonomous zinc-finger nuclease pairs for targeted chromosomal deletion. Nucleic Acids Res. 38, 8269–8276 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Szczepek, M. et al. Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases. Nat. Biotechnol. 25, 786–793 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Miller, J.C. et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nat. Biotechnol. 25, 778–785 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Maeder, M.L. et al. Rapid “open-source” engineering of customized zinc-finger nucleases for highly efficient gene modification. Mol. Cell 31, 294–301 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Urnov, F.D., Rebar, E.J., Holmes, M.C., Zhang, H.S. & Gregory, P.D. Genome editing with engineered zinc finger nucleases. Nat. Rev. Genet. 11, 636–646 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Miller, J.C. et al. Improved specificity of TALE-based genome editing using an expanded RVD repertoire. Nat. Methods 12, 465–471 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Juillerat, A. et al. Optimized tuning of TALEN specificity using non-conventional RVDs. Sci. Rep. 5, 8150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Guilinger, J.P. et al. Broad specificity profiling of TALENs results in engineered nucleases with improved DNA-cleavage specificity. Nat. Methods 11, 429–435 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cho, S.W., Kim, S., Kim, J.M. & Kim, J.S. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat. Biotechnol. 31, 230–232 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cradick, T.J., Fine, E.J., Antico, C.J. & Bao, G. CRISPR/Cas9 systems targeting β-globin and CCR5 genes have substantial off-target activity. Nucleic Acids Res. 41, 9584–9592 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jinek, M. et al. RNA-programmed genome editing in human cells. eLife 2, e00471 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pattanayak, V. et al. High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity. Nat. Biotechnol. 31, 839–843 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mali, P., Esvelt, K.M. & Church, G.M. Cas9 as a versatile tool for engineering biology. Nat. Methods 10, 957–963 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tsai, S.Q. & Joung, J.K. Defining and improving the genome-wide specificities of CRISPR-Cas9 nucleases. Nat. Rev. Genet. 17, 300–312 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Slaymaker, I.M. et al. Rationally engineered Cas9 nucleases with improved specificity. Science 351, 84–88 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Kleinstiver, B.P. et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature 529, 490–495 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ran, F.A. et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186–191 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Müller, M. et al. Streptococcus thermophilus CRISPR-Cas9 systems enable specific editing of the human genome. Mol. Ther. 24, 636–644 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lee, C.M., Cradick, T.J. & Bao, G. The Neisseria meningitidis CRISPR-Cas9 system enables specific genome editing in mammalian cells. Mol. Ther. 24, 645–654 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kleinstiver, B.P. et al. Genome-wide specificities of CRISPR-Cas Cpf1 nucleases in human cells. Nat. Biotechnol. 34, 869–874 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim, D. et al. Genome-wide analysis reveals specificities of Cpf1 endonucleases in human cells. Nat. Biotechnol. 34, 863–868 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Ramirez, C.L. et al. Engineered zinc finger nickases induce homology-directed repair with reduced mutagenic effects. Nucleic Acids Res. 40, 5560–5568 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ran, F.A. et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154, 1380–1389 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Luo, Y. et al. Generation of TALE nickase-mediated gene-targeted cows expressing human serum albumin in mammary glands. Sci. Rep. 6, 20657 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Komor, A.C., Kim, Y.B., Packer, M.S., Zuris, J.A. & Liu, D.R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Carroll, D. Genome engineering with targetable nucleases. Annu. Rev. Biochem. 83, 409–439 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Sander, J.D. & Joung, J.K. CRISPR-Cas systems for editing, regulating and targeting genomes. Nat. Biotechnol. 32, 347–355 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ousterout, D.G. et al. Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat. Commun. 6, 6244 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Amabile, A. et al. Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell 167, 219–232.e214 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tsai, S.Q. et al. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat. Biotechnol. 33, 187–197 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Kim, D. et al. Digenome-seq: genome-wide profiling of CRISPR-Cas9 off-target effects in human cells. Nat. Methods 12, 237–243 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Lee, C.M., Cradick, T.J., Fine, E.J. & Bao, G. Nuclease target site selection for maximizing on-target activity and minimizing off-target effects in genome editing. Mol. Ther. 24, 475–487 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Baum, C. et al. Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol. Ther. 9, 5–13 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Mussolino, C. et al. A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Res. 39, 9283–9293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Miller, J.C. et al. A TALE nuclease architecture for efficient genome editing. Nat. Biotechnol. 29, 143–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Mussolino, C. & Cathomen, T. TALE nucleases: tailored genome engineering made easy. Curr. Opin. Biotechnol. 23, 644–650 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Cho, S.W. et al. Analysis of off-target effects of CRISPR/Cas-derived RNA-guided endonucleases and nickases. Genome Res. 24, 132–141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tsai, S.Q. et al. Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing. Nat. Biotechnol. 32, 569–576 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Canver, M.C. et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527, 192–197 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Avalle, L., Pensa, S., Regis, G., Novelli, F. & Poli, V. STAT1 and STAT3 in tumorigenesis: A matter of balance. JAK-STAT 1, 65–72 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Pike-Overzet, K. et al. Successful RAG1-SCID gene therapy depends on the level of RAG1 expression. J. Allergy Clin. Immunol. 134, 242–243 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Ding, W. et al. Zinc finger nucleases targeting the human papillomavirus E7 oncogene induce E7 disruption and a transformed phenotype in HPV16/18-positive cervical cancer cells. Clin. Cancer Res. 20, 6495–6503 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. 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. 21, 1889–1897 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Holt, N. et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat. Biotechnol. 28, 839–847 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Perez, E.E. et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat. Biotechnol. 26, 808–816 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Su, S. et al. CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells from cancer patients. Sci. Rep. 6, 20070 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Valton, J. et al. A multidrug-resistant engineered CAR T cell for allogeneic combination immunotherapy. Mol. Ther. 23, 1507–1518 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Provasi, E. et al. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat. Med. 18, 807–815 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lombardo, A. et al. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat. Biotechnol. 25, 1298–1306 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Yang, Y. et al. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat. Biotechnol. 34, 334–338 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all members of the laboratories for helpful discussion. Current research in our labs is funded by the Federal Ministry of Education and Research (IFB—01EO0803; iMACnet—01EK1602B; HBV-TALE—01DG15005), the German Research Foundation (SFB1160—TP17), the European Commission's Horizon 2020 Program (SCIDNET—666908; CARAT—667980), Casebia Therapeutics (CAU-950-20140702) and the German Academic Exchange Service.

Author information

Authors and Affiliations

  1. Institute for Cell and Gene Therapy, Medical Center—University of Freiburg, Freiburg, Germany

    Tatjana I Cornu, Claudio Mussolino & Toni Cathomen

  2. Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany

    Tatjana I Cornu, Claudio Mussolino & Toni Cathomen

  3. Faculty of Medicine, University of Freiburg, Freiburg, Germany.,

    Toni Cathomen

Authors
  1. Tatjana I Cornu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudio Mussolino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toni Cathomen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toni Cathomen.

Ethics declarations

Competing interests

T.C. is a consultant for TRACR Hematology.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cornu, T., Mussolino, C. & Cathomen, T. Refining strategies to translate genome editing to the clinic. Nat Med 23, 415–423 (2017). https://doi.org/10.1038/nm.4313

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4313

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research