The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
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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“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]
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Cites
The Sequence Alignment/Map format and SAMtools
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Self-citationA human memory T cell subset with stem cell–like properties
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TALENs: A widely applicable technology for targeted genome editing
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“Artificial endonucleases, such as Zinc Finger Nucleases (ZFNs) 11 , Transcription Activator-Like Effector Nucleases (TALENs) 12 , and RNA-guided nucleases (CRISPR/Cas) 13 brought the possibility of gene targeting within the reach of gene therapy 14,15 .”
Highly efficient endogenous human gene correction using designed zinc-finger nucleases
Urnov, F. D., Miller, J. C., Lee, Y.-L., Beausejour, C. M., Rock, J. M., Augustus, S., Jamieson, A. C., Porteus, M. H., Gregory, P. D., & Holmes, M. C. (2005) · Nature · doi:10.1038/nature03556 · Cited by 1,642
Self-citationHematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy
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“Hematopoietic Stem Cells (HSC)-based gene therapy has provided therapeutic benefit in primary immunodeficiencies 1,2 , thalassemia 3 and leukodystrophies 4,5 .”
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Dunbar, C. E., High, K. A., Joung, J. K., Kohn, D. B., Ozawa, K., & Sadelain, M. (2018) · Science · doi:10.1126/science.aan4672 · Cited by 1,410
Therapeutic genome editing: prospects and challenges
Cox, D. B. T., Platt, R. J., & Zhang, F. (2015) · Nature Medicine · doi:10.1038/nm.3793 · Cited by 1,336
Gene therapy returns to centre stage
Naldini, L. (2015) · Nature · doi:10.1038/nature15818 · Cited by 1,184
Self-citationIn vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration
Suzuki, K., Tsunekawa, Y., Hernandez-Benitez, R., Wu, J., Zhu, J., Kim, E. J., Hatanaka, F., Yamamoto, M., Araoka, T., Li, Z., et al. (2016) · Nature · doi:10.1038/nature20565 · Cited by 1,150
Richardson, C. D., Ray, G. J., DeWitt, M. A., Curie, G. L., & Corn, J. E. (2016) · Nature Biotechnology · doi:10.1038/nbt.3481 · Cited by 1,098
Metadata
- 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)
- Erasmus MC (NL)
- 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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