A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition
Open accessAbstract
Disorders resulting from mutations in the hemoglobin subunit beta gene (HBB; which encodes β-globin), mainly sickle cell disease (SCD) and β-thalassemia, become symptomatic postnatally as fetal γ-globin expression from two paralogous genes, hemoglobin subunit gamma 1 (HBG1) and HBG2, decreases and adult β-globin expression increases, thereby shifting red blood cell (RBC) hemoglobin from the fetal (referred to as HbF or α2γ2) to adult (referred to as HbA or α2β2) form. These disorders are alleviated when postnatal expression of fetal γ-globin is maintained. For example, in hereditary persistence of fetal hemoglobin (HPFH), a benign genetic condition, mutations attenuate γ-globin-to-β-globin switching, causing high-level HbF expression throughout life. Co-inheritance of HPFH with β-thalassemia- or SCD-associated gene mutations alleviates their clinical manifestations. Here we performed CRISPR–Cas9-mediated genome editing of human blood progenitors to mutate a 13-nt sequence that is present in the promoters of the HBG1 and HBG2 genes, thereby recapitulating a naturally occurring HPFH-associated mutation. Edited progenitors produced RBCs with increased HbF levels that were sufficient to inhibit the pathological hypoxia-induced RBC morphology found in SCD. Our findings identify a potential DNA target for genome-editing-mediated therapy of β-hemoglobinopathies.
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It 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 [25]
The main text (page unavailable) reports CRISPR/Cas9 editing of CD34+ HSPCs and increased fetal hemoglobin in their cultured erythroid progeny. It does not show correction of the disease-causing mutation or long-term engraftment; the Methods describe in-vitro differentiation rather than a transplantation study. (LLM, conf=0.88)
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“The bacterial type II CRISPR Cas system has been efficiently exploited to edit a variety of genomes and has recently gained prominence for gene therapy applications, predominantly for monogenic disorders like beta thalassemia and sickle cell anemia (39-40).”
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“Among these, human HbF is the major hemoglobin in fetal RBCs and is almost completely replaced by HbA within a year by switching from γ -globin gene ( HBG ) to HBB gene expression [34,36].”
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“Along with genetic improvement, several gene therapies for the treatment of hemoglobinopathies are currently in clinical trials or under development, including therapies utilizing gene replacement therapy using lentiviruses and the latest gene editing techniques [86-88].”
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Self-citationActivation of γ-globin expression by hypoxia-inducible factor 1α
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Self-citationGene editing and its applications in biomedicine
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“ulatory elements of the γ-globin promoter (−112 to −117) region (Traxler et al., 2016) or of the +58 enhancer of a γglobin repressor, namely, BCL11A (Canver et al.”
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Engineered Nanomaterials to Potentiate CRISPR/Cas9 Gene Editing for Cancer Therapy
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Sickle cell disease in the older adult
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“Two groups recently published successful gene deletions as a gene therapy approach to cure sickle cell disease, a common inherited blood disorder.(17,18) It should be noted that AAV-based expression constructs may induce anti-viral host immune responses and may non-specifically integrate into the host genome.”
BackgroundDoerfler, P. A., Feng, R.-P., Li, Y.-C., Palmer, L., Porter, S. N., Bell, H. W., Crossley, M., Pruett-Miller, S., Cheng, Y., & Weiss, M. (2021) · Nature Genetics · doi:10.1038/s41588-021-00904-0 · Cited by 56 · see citing works
Self-citationBionanomaterials based on protein self-assembly: Design and applications in biotechnology
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ON-Target Adverse Events of CRISPR-Cas9 Nuclease: More Chaotic than Expected
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“63 These deletions were detected by qPCR and fluorescence in situ hybridization (FISH).”
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Self-citationGene Therapy for Hemoglobinopathies
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“With a β/g-globin expression profile of <1% g-globin and >95% β-globin, very similar to adult erythroid cells, the HUDEP-2 line has become a useful model system for studying globin switching.(11,13,38) Based on the 10-20-fold increase in g-globin gene expression in β-YAC mice lacking MBD2,(32) we hypothesized that the…”
BackgroundSelf-citationSingle-nucleotide-level mapping of DNA regulatory elements that control fetal hemoglobin expression
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Self-citationCurrent trends of clinical trials involving CRISPR/Cas systems
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“Hereditary persistence of fetal hemoglobin (HPFH) is a naturally occurring benign condition mostly caused by point mutations and deletions in the β -globin cluster that repress the γ -globin to β -globin switch, resulting in the elevation of HbF in adult erythrocytes (92).”
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Gene Therapy Approaches to Hemoglobinopathies
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Gene Therapy For Beta-Thalassemia: Updated Perspectives
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Adenovirus vectors in hematopoietic stem cell genome editing
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Self-citationThalassemias: from gene to therapy
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Genetic modifiers of fetal haemoglobin in sickle cell disease
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CRISPR-Mediated Editing of the B Cell Receptor in Primary Human B Cells
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“CRISPR-mediated ex vivo genome editing has been applied to correct the gene encoding hemoglobin in hematopoietic stem cells (HSCs) and/or progenitor cells, providing an innovative path to address b-hemo- globinopathies (Dever et al., 2016; Traxler et al., 2016).”
MethodRecent Advances in CRISPR/Cas9 Delivery Approaches for Therapeutic Gene Editing of Stem Cells
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“Generation of this canonical deletion likely occurs due to a high degree of microhomology within surrounding sequences that increase the likelihood of DNA repair events that resolve with this specific sequence.(13) d13 HPFH subjects express fetal hemoglobin at levels that abrogate the sickle phenotype.”
Evolution of hemoglobin loci and their regulatory elements
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“to substantial increase in fetal hemoglobin and reduced sickling in cells derived from sickle cell patients [105].”
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“This is consistent with our hypothesis that the efficacy of HBG/BCL11A axis disruption is highly dependent on the particular type of indel formed, supported by a previous report demonstrating that a single nucleotide insertion at HBG-113 may allow the core CCAAT box to be preserved and therefore was not associated wit…”
ResultCruz, L. J., van Dijk, T., Vepris, O., Li, T. M. W. Y., Schomann, T., Baldazzi, F., Kurita, R., Nakamura, Y., Grosveld, F. G., Philipsen, S., et al. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120580 · Cited by 50 · see citing works
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- Authors
- Traxler, E. A., Yao, Y., Wang, Y.-D., Woodard, K. J., Kurita, R., Nakamura, Y., Hughes, J. R., Hardison, R. C., Blobel, G. A., Li, C., & Weiss, M. J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- RIKEN BioResource Research Center (JP)
- University of Tsukuba (JP)
- University of Oxford (GB)
- Pennsylvania State University (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Weiss, Mitchell J
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-08-15
- Volume
- 22
- Issue
- 9
- Pages
- 987-990
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5706766
- OpenAlex
- W2511090954
- Semantic Scholar
- 1667b168571a1418041ee025a37d4f39444fd941
- Cited by
- 366
- References
- 21
- Citations by year
- 2026: 20 · 2025: 27 · 2024: 27 · 2023: 30 · 2022: 24 · 2021: 50 · 2020: 64 · 2019: 38 · 2018: 51 · 2017: 30 · 2016: 5
- FWCI
- 29.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL119479)
- National Cancer Institute (P30CA021765)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK065806, F30DK102291, R24DK106766)
- 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
- β-hemoglobinopathies, sickle cell disease, beta-thalassemia, hereditary persistence of fetal hemoglobin, CRISPR/Cas9 genome editing, fetal hemoglobin, beta-globin gene, erythrocyte morphology, hypoxia, gene therapy
- MeSH terms
- Gene Editing, Anemia, Sickle Cell, Fetal Hemoglobin, Hemoglobin A, Humans, Mutation, Promoter Regions, Genetic, RNA, Messenger, Erythroid Precursor Cells, Mutagenesis, Site-Directed, beta-Thalassemia, In Situ Hybridization, Fluorescence, Reverse Transcriptase Polymerase Chain Reaction, beta-Globins, gamma-Globins, CRISPR-Cas Systems
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