CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes
Open accessAbstract
Genome editing tools such as the clustered regularly interspaced short palindromic repeat (CRISPR)-associated system (Cas) have been widely used to modify genes in model systems including animal zygotes and human cells, and hold tremendous promise for both basic research and clinical applications. To date, a serious knowledge gap remains in our understanding of DNA repair mechanisms in human early embryos, and in the efficiency and potential off-target effects of using technologies such as CRISPR/Cas9 in human pre-implantation embryos. In this report, we used tripronuclear (3PN) zygotes to further investigate CRISPR/Cas9-mediated gene editing in human cells. We found that CRISPR/Cas9 could effectively cleave the endogenous β-globin gene (HBB). However, the efficiency of homologous recombination directed repair (HDR) of HBB was low and the edited embryos were mosaic. Off-target cleavage was also apparent in these 3PN zygotes as revealed by the T7E1 assay and whole-exome sequencing. Furthermore, the endogenous delta-globin gene (HBD), which is homologous to HBB, competed with exogenous donor oligos to act as the repair template, leading to untoward mutations. Our data also indicated that repair of the HBB locus in these embryos occurred preferentially through the non-crossover HDR pathway. Taken together, our work highlights the pressing need to further improve the fidelity and specificity of the CRISPR/Cas9 platform, a prerequisite for any clinical applications of CRSIPR/Cas9-mediated editing.
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The reported efficiencies of repair with templates in human embryos are very low.
“Of the studies that have been conducted, the reported efficiencies of repair with templates in human embryos are very low (5,7,8).”
From Frequent loss of heterozygosity in CRISPR-Cas9–edited early human embryos (2021) · cites this paper as [5]
Current clinical trials using the CRISPR platform aim to improve CAR T-cell effectiveness, treat sickle cell disease and other inherited blood disorders, and stop or reverse eye disease.
“Current clinical trials using the CRISPR platform aim to improve chimeric antigen receptor (CAR) T-cell effectiveness, treat sickle cell disease and other inherited blood disorders, and stop or reverse eye disease 109 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [109]
The Abstract and Results describe CRISPR/Cas9 editing of HBB in human cells and tripronuclear zygotes, not clinical trials. Searches for CAR T cells, sickle cell disease, inherited blood disorders, and eye disease found no passage describing the claimed trial aims. (LLM, conf=0.77)
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- Authors
- Liang, P., Xu, Y., Zhang, X., Ding, C., Huang, R., Zhang, Z., Lv, J., Xie, X., Chen, Y., Li, Y., Sun, Y., Bai, Y., Songyang, Z., Ma, W., Zhou, C., & Huang, J.
- Affiliations
- Sun Yat-sen University (CN)
- Corresponding author
- Zhou, Canquan
- Huang, Junjiu
- ORCID
- Venue
- Protein & Cell
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-04-18
- Volume
- 6
- Issue
- 5
- Pages
- 363-372
- ISSN
- 1674-800X (ISSN-L)
- 1674-8018
- PMC
- PMC4417674
- OpenAlex
- W2141825721
- Cited by
- 1,135
- References
- 58
- Citations by year
- 2026: 33 · 2025: 46 · 2024: 60 · 2023: 57 · 2022: 55 · 2021: 87 · 2020: 111 · 2019: 122 · 2018: 151 · 2017: 150 · 2016: 160 · 2015: 102 · 2013: 1
- FWCI
- 81.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Protein & Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (91019020, 973 Program, 31371508, 81330055, 2010CB945401)
- National Key Research and Development Program of China (2010CB945401, 2012CB911201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- CRISPR/Cas9, genome editing, preimplantation embryo, homologous recombination repair, off-target cleavage, HBB, HBD, embryo mosaicism, DNA repair mechanisms, beta-globin
- MeSH terms
- Blastocyst, Hemoglobins, Abnormal, Humans, Zygote, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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