Targeted genome editing in human repopulating haematopoietic stem cells

Genovese, Pietro, Schiroli, Giulia, Escobar, Giulia, Di Tomaso, Tiziano, Firrito, Claudio, Calabria, Andrea, Moi, Davide, Mazzieri, Roberta, Bonini, Chiara, Holmes, Michael C., Gregory, Philip D., van der Burg, Mirjam, Gentner, Bernhard, Montini, Eugenio, Lombardo, Angelo and Naldini, Luigi (2014) Targeted genome editing in human repopulating haematopoietic stem cells. Nature, 510 7504: 235-240. doi:10.1038/nature13420

Author Genovese, Pietro
Schiroli, Giulia
Escobar, Giulia
Di Tomaso, Tiziano
Firrito, Claudio
Calabria, Andrea
Moi, Davide
Mazzieri, Roberta
Bonini, Chiara
Holmes, Michael C.
Gregory, Philip D.
van der Burg, Mirjam
Gentner, Bernhard
Montini, Eugenio
Lombardo, Angelo
Naldini, Luigi
Title Targeted genome editing in human repopulating haematopoietic stem cells
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
Publication date 2014-06-12
Year available 2014
Sub-type Article (original research)
DOI 10.1038/nature13420
Open Access Status Not Open Access
Volume 510
Issue 7504
Start page 235
End page 240
Total pages 6
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 158 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 170 times in Scopus Article | Citations
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