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Targeted genome editing in human repopulating haematopoietic stem cells

Author

Listed:
  • Pietro Genovese

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy)

  • Giulia Schiroli

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy
    Vita Salute San Raffaele University, 20132 Milan, Italy)

  • Giulia Escobar

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy
    Vita Salute San Raffaele University, 20132 Milan, Italy)

  • Tiziano Di Tomaso

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy)

  • Claudia Firrito

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy)

  • Andrea Calabria

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy)

  • Davide Moi

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy
    Present address: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia.)

  • Roberta Mazzieri

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy
    Present address: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia.)

  • Chiara Bonini

    (Experimental Hematology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy)

  • Michael C. Holmes

    (Sangamo BioSciences Inc.)

  • Philip D. Gregory

    (Sangamo BioSciences Inc.)

  • Mirjam van der Burg

    (University Medical Center, 3015 Rotterdam, The Netherlands)

  • Bernhard Gentner

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy
    Vita Salute San Raffaele University, 20132 Milan, Italy)

  • Eugenio Montini

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy)

  • Angelo Lombardo

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy
    Vita Salute San Raffaele University, 20132 Milan, Italy)

  • Luigi Naldini

    (TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy
    Vita Salute San Raffaele University, 20132 Milan, Italy)

Abstract

Targeted genome editing by artificial nucleases has brought the goal of site-specific transgene integration and gene correction within the reach of gene therapy. However, its application to long-term repopulating haematopoietic stem cells (HSCs) has remained elusive. Here we show that poor permissiveness to gene transfer and limited proficiency of the homology-directed DNA repair pathway constrain gene targeting in human HSCs. By tailoring delivery platforms and culture conditions we overcame these barriers and provide stringent evidence of targeted integration in human HSCs by long-term multilineage repopulation of transplanted mice. We demonstrate the therapeutic potential of our strategy by targeting a corrective complementary DNA into the IL2RG gene of HSCs from healthy donors and a subject with X-linked severe combined immunodeficiency (SCID-X1). Gene-edited HSCs sustained normal haematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RG mutations. These results open up new avenues for treating SCID-X1 and other diseases.

Suggested Citation

  • Pietro Genovese & Giulia Schiroli & Giulia Escobar & Tiziano Di Tomaso & Claudia Firrito & Andrea Calabria & Davide Moi & Roberta Mazzieri & Chiara Bonini & Michael C. Holmes & Philip D. Gregory & Mir, 2014. "Targeted genome editing in human repopulating haematopoietic stem cells," Nature, Nature, vol. 510(7504), pages 235-240, June.
  • Handle: RePEc:nat:nature:v:510:y:2014:i:7504:d:10.1038_nature13420
    DOI: 10.1038/nature13420
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    Cited by:

    1. Ron Baik & M. Kyle Cromer & Steve E. Glenn & Christopher A. Vakulskas & Kay O. Chmielewski & Amanda M. Dudek & William N. Feist & Julia Klermund & Suzette Shipp & Toni Cathomen & Daniel P. Dever & Mat, 2024. "Transient inhibition of 53BP1 increases the frequency of targeted integration in human hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Sebastian M. Siegner & Laura Ugalde & Alexandra Clemens & Laura Garcia-Garcia & Juan A. Bueren & Paula Rio & Mehmet E. Karasu & Jacob E. Corn, 2022. "Adenine base editing efficiently restores the function of Fanconi anemia hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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