Targeted genome editing in human repopulating haematopoietic stem cells
Open accessAbstract
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.
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The HDR pathway is not highly active in human cells, limiting clinical efficacy of HDR-based CFTR repair.
“Nevertheless, the HDR pathway is not highly active in human cells, thus strongly limiting the clinical efficacy of this application23,24.”
From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [24]
The Discussion (page unavailable) reports that primitive human haematopoietic stem cells are less proficient at HDR than committed progenitors, and that a potentially limited number of targeted cells could affect clinical correction of SCID-X1. It does not establish low HDR activity in human cells generally or assess the clinical efficacy of HDR-based CFTR repair. (LLM, conf=0.86)
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- Authors
- Genovese, P., Schiroli, G., Escobar, G., Di Tomaso, T., Firrito, C., Calabria, A., Moi, D., Mazzieri, R., Bonini, C., Holmes, M. C., Gregory, P. D., van der Burg, M., Gentner, B., Montini, E., Lombardo, A., & Naldini, L.
- Affiliations
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Vita-Salute San Raffaele University (IT)
- IRCCS Ospedale San Raffaele (IT)
- Sangamo BioSciences (United States) (US)
- Corresponding author
- Naldini, Luigi
- ORCID
- Venue
- Nature
- Published
- 2014-05-28
- Volume
- 510
- Issue
- 7504
- Pages
- 235-240
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4082311
- OpenAlex
- W1995497292
- Cited by
- 555
- References
- 44
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 23 · 2023: 32 · 2022: 42 · 2021: 51 · 2020: 43 · 2019: 50 · 2018: 57 · 2017: 57 · 2016: 71 · 2015: 77 · 2014: 24
- FWCI
- 28.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- targeted genome editing, hematopoietic stem cells, homology-directed repair, gene targeting, IL2RG, X-linked severe combined immunodeficiency, gene therapy, transgene integration
- MeSH terms
- Animals, Endonucleases, Fetal Blood, Hematopoiesis, Hematopoietic Stem Cells, Humans, Male, Mutation, Genome, Human, DNA, Complementary, Hematopoietic Stem Cell Transplantation, Gene Targeting, Antigens, CD34, Mice, Targeted Gene Repair, Interleukin Receptor Common gamma Subunit, X-Linked Combined Immunodeficiency Diseases
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