Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells
Open accessAbstract
Key Points: Delivery of ZFNs and donor templates results in high levels of gene correction in human CD34+ cells from multiple sources, including SCD BM. Modified CD34+ cells are capable of engrafting immunocompromised NSG mice and produce cells from multiple lineages.
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It notes that multiple reports have achieved efficient Glu6Val correction in SCD HSPCs, though off-target insertions or deletions can accompany correction.
“Accordingly, several reports have shown efficient Glu6Val correction in SCD-HSPCs, although correction efficiency can sometimes be linked with off-target INDELs in the same edited population15,16,45,46.”
From A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells (2018) · cites this paper as [45]
The Gene correction in sickle BM section reports correction of the sickle mutation in patient-derived HSPCs. The Comprehensive ZFN specificity assessment reports off-target modification at the δ-globin gene in SCD bone-marrow CD34+ cells, but the passages do not establish that those off-target modifications were specifically INDELs; the indels shown alongside correction in Figure 5 are at the target β-globin cut site. (LLM, conf=0.83)
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- Authors
- Hoban, M. D., Cost, G. J., Mendel, M. C., Romero, Z., Kaufman, M. L., Joglekar, A. V., Ho, M., Lumaquin, D., Gray, D., Lill, G. R., Cooper, A. R., Urbinati, F., Senadheera, S., Zhu, A., Liu, P.-Q., Paschon, D. E., Zhang, L., Rebar, E. J., Wilber, A., Wang, X., Gregory, P. D., Holmes, M. C., Reik, A., Hollis, R. P., & Kohn, D. B.
- Affiliations
- University of California, Los Angeles (US)
- Sangamo BioSciences (United States) (US)
- Sangamo BioSciences Inc., Richmond, CA;
- SIU Medicine (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2015-04-23
- Volume
- 125
- Issue
- 17
- Pages
- 2597-2604
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC4408287
- OpenAlex
- W2001887791
- Semantic Scholar
- 1722082bb8ed43890c1e142368586c088682400e
- Cited by
- 320
- References
- 31
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 17 · 2023: 17 · 2022: 16 · 2021: 41 · 2020: 34 · 2019: 24 · 2018: 40 · 2017: 41 · 2016: 55 · 2015: 20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Doris Duke Charitable Foundation
- California Institute for Regenerative Medicine (TR4-06823, CIRM TR4-06823)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01HL073104)
- National Institute of General Medical Sciences (GM 007185, GM55052, T32GM007185, R25GM055052)
- National Institute of Allergy and Infectious Diseases (T32AI060567)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- 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
- Keywords
- sickle cell disease, beta-globin gene, zinc finger nucleases, gene correction, hematopoietic stem and progenitor cells, CD34+ cells, homologous recombination, integrase-defective lentiviral vectors, off-target cleavage
- MeSH terms
- Anemia, Sickle Cell, Animals, Base Sequence, Bone Marrow Cells, Cells, Cultured, Endodeoxyribonucleases, Fetal Blood, Hematopoietic Stem Cells, Humans, Molecular Sequence Data, Mutation, Genetic Therapy, Zinc Fingers, Mice, SCID, Mice, Inbred NOD, Hematopoietic Stem Cell Transplantation, Antigens, CD34, Mice, beta-Globins, Genetic Loci
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