CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells
Open accessAbstract
The β-haemoglobinopathies, such as sickle cell disease and β-thalassaemia, are caused by mutations in the β-globin (HBB) gene and affect millions of people worldwide. Ex vivo gene correction in patient-derived haematopoietic stem cells followed by autologous transplantation could be used to cure β-haemoglobinopathies. Here we present a CRISPR/Cas9 gene-editing system that combines Cas9 ribonucleoproteins and adeno-associated viral vector delivery of a homologous donor to achieve homologous recombination at the HBB gene in haematopoietic stem cells. Notably, we devise an enrichment model to purify a population of haematopoietic stem and progenitor cells with more than 90% targeted integration. We also show efficient correction of the Glu6Val mutation responsible for sickle cell disease by using patient-derived stem and progenitor cells that, after differentiation into erythrocytes, express adult β-globin (HbA) messenger RNA, which confirms intact transcriptional regulation of edited HBB alleles. Collectively, these preclinical studies outline a CRISPR-based methodology for targeting haematopoietic stem cells by homologous recombination at the HBB locus to advance the development of next-generation therapies for β-haemoglobinopathies.
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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 [15]
The ‘HBB gene correction in SCD HSPCs’ section reports correction of an average of 50% of E6V alleles in patient-derived HSPCs, so this paper supports the efficient-correction part as one of the cited reports. The Extended Data describe off-target INDEL measurements in CD34+ HSPCs, but do not link those INDELs to correction in the same SCD-HSPC population; the INDELs reported alongside SCD correction were measured at the on-target HBB locus. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIt reports that ribonucleoprotein delivery gives a brief pulse of editing machinery, producing efficient editing with fewer off-target effects.
“RNP delivery results in an initially high level of the genome editing machinery followed by rapid decay, leading to a “fast on, fast off” strategy that results in highly efficient editing while minimizing OTEs13–19.”
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 [15]
The Abstract reports efficient HBB editing in human HSPCs using Cas9 RNPs, and the Extended Data report greater on-target versus off-target specificity for RNP delivery than for an all-RNA system. Neither passage establishes an initially high level of editing machinery followed by rapid decay, or shows that this timing causes the improved specificity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIt states that AAV6 donor templates with homology arms efficiently deliver donor DNA into sensitive primary immune cells such as HSPCs and T cells.
“AAV6 homologous donor DNA templates are an efficient way to deliver donor templates for sensitive primary immune cells, including HSPCs and T-Cells15,35–40.”
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 [15]
The section “CRISPR/Cas9 targeted HBB gene editing in HSPCs” reports high HSPC transduction and stable GFP expression in an average of 29% of HSPCs after delivery of homologous ssAAV6 donors. The paper supports the HSPC part of the claim, but the passages found do not establish efficient donor delivery in T cells. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIt cites prior work showing that CRISPR/Cas9 can correct disease-causing mutations in long-term engrafting HSPCs that persist in downstream lineages.
“Recent studies have shown that disease-causing genetic errors can be corrected using CRISPR/Cas9 in long-term engrafting HSPCs that are preserved in downstream effector lineages15,16,24,25.”
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 [15]
The “HBB gene correction in SCD HSPCs” section reports correction of the disease-causing E6V mutation in patient-derived HSPCs and expression of corrected β-globin in erythrocytes differentiated from them in vitro. The “HBB targeting in long-term repopulating HSCs” section reports edited cells in downstream lineages and secondary transplant recipients, but those experiments tracked HBB targeting with reporter donors, not correction of the disease-causing mutation. The paper therefore does not show that mutation-corrected cells themselves persisted through long-term engraftment into downstream lineages. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMajor progress in delivering to and handling HPSCs has resulted in formidable efficiencies of mutation correction or mitigation that are expected to be curative.
“Major progress in delivering to 44 and handling HPSCs has resulted in formidable efficiencies of mutation correction or mitigation 18,45-47 that are expected to be curative.”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [45]
The HBB gene correction section (page unavailable) reports correction of an average of 50% of sickle-cell alleles in patient-derived HSPCs, supporting the claim of substantial editing efficiency. The Discussion (page unavailable) says future studies must determine whether the engraftment levels of HBB-modified cells would be clinically beneficial; it does not establish that the achieved efficiencies are expected to be curative. (LLM, conf=0.88)
Experimental — accuracy not yet measured
CRISPR/Cas9 system holds tremendous promise for gene therapy and can correct causal mutations in the original genome and rescue disease phenotypes of monogenic disorders permanently.
“Furthermore, CRISPR/Cas9 system holds tremendous promise for gene therapy [46–51]. It can correct causal mutations in the original genome and rescue the disease phenotypes of monogenic disorders permanently, which currently represents the most translatable field in CRISPR/Cas9-mediated disease therapy.”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [49]
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Self-citation
- Authors
- Dever, D. P., Bak, R. O., Reinisch, A., Camarena, J., Washington, G., Nicolas, C. E., Pavel-Dinu, M., Saxena, N., Wilkens, A. B., Mantri, S., Uchida, N., Hendel, A., Narla, A., Majeti, R., Weinberg, K. I., & Porteus, M. H.
- Affiliations
- Stanford University (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Stanford Medicine (US)
- Corresponding author
- Porteus, Matthew H.
- ORCID
- Venue
- Nature
- Published
- 2016-11-07
- Volume
- 539
- Issue
- 7629
- Pages
- 384-389
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5898607
- OpenAlex
- W2547418311
- Semantic Scholar
- 91eb4c33902b14df9b2974a4ce8dc6e3c3a02125
- Cited by
- 864
- References
- 50
- Citations by year
- 2026: 45 · 2025: 75 · 2024: 80 · 2023: 93 · 2022: 76 · 2021: 120 · 2020: 93 · 2019: 90 · 2018: 99 · 2017: 89 · 2016: 4
- FWCI
- 48.84
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (5r01ai120766-02, R01-AI120766)
- National Eye Institute (PN2EY018244)
- National Institute of General Medical Sciences (T32GM007266)
- National Institute of Allergy and Infectious Diseases (R01-AI120766, R01AI097320)
- 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 › Genetics › Hemoglobinopathies and Related Disorders
- Keywords
- CRISPR/Cas9 genome editing, beta-globin gene, hematopoietic stem cells, sickle cell disease, beta-thalassemia, homologous recombination, adeno-associated virus vectors, Cas9 ribonucleoprotein, autologous transplantation, reporter genes
- MeSH terms
- Gene Editing, Dependovirus, Alleles, Anemia, Sickle Cell, Animals, Cell Differentiation, Cell Separation, Erythrocytes, Female, Flow Cytometry, Hematopoietic Stem Cells, Humans, Microspheres, Mutation, RNA, Messenger, Genetic Therapy, Mice, SCID, Mice, Inbred NOD, beta-Thalassemia, Genes, Reporter, Gene Targeting, Antigens, CD34, Cell Lineage, beta-Globins, Magnets, Homologous Recombination, CRISPR-Cas Systems, CRISPR-Associated Proteins
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