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Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells
- Source :
- Nature, Nature, 510(7504), 235-+. Nature Publishing Group
- Publication Year :
- 2014
-
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.
- Subjects :
- Male
DNA, Complementary
Genetic enhancement
Transgene
Antigens, CD34
Biology
Gene delivery
X-Linked Combined Immunodeficiency Diseases
Article
Mice
03 medical and health sciences
0302 clinical medicine
SDG 3 - Good Health and Well-being
Genome editing
Animals
Humans
030304 developmental biology
Genetics
0303 health sciences
Transcription activator-like effector nuclease
Multidisciplinary
Genome, Human
Hematopoietic Stem Cell Transplantation
Gene targeting
Endonucleases
Fetal Blood
Hematopoietic Stem Cells
Hematopoiesis
Cell biology
Haematopoiesis
030220 oncology & carcinogenesis
Mutation
Gene Targeting
Stem cell
Interleukin Receptor Common gamma Subunit
Targeted Gene Repair
Subjects
Details
- Language :
- English
- ISSN :
- 14764687 and 00280836
- Volume :
- 510
- Issue :
- 7504
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....2bd42ad468e0dd0a71e6f47c28b390f6