ArticleThe Journal of clinical investigation2020
BCL11A enhancer-edited hematopoietic stem cells persist in rhesus monkeys without toxicity.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 66 citations in OpenAlex.
- Zinc finger nuclease-mediated gene editing in hematopoietic stem cells results in reactivation of fetal hemoglobin in sickle cell disease.Scientific reports · 2024Trial
- Engineered lipid nanoparticles for in vivo and durable editing of haematopoietic stem cells within humanized mice.Nature biomedical engineering · 2026Article
- Engraftment of gene-edited hematopoietic stem cells after antibody-drug conjugate conditioning in nonhuman primates.Blood advances · 2026Article
- Comparative analysis of CRISPR-Cas9, lentiviral transduction, and base editing for sickle cell disease in a murine model.Blood advances · 2026Article
- GroβT rapidly and reliably mobilizes primitive hematopoietic stem and progenitor cells in nonhuman primates.Molecular therapy. Methods & clinical development · 2025Article
- Nonclinical evaluation of HBG1/2 and BCL11A as genome-editing targets for the treatment of β-hemoglobinopathies.Blood advances · 2025Article
- Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.Cell stem cell · 2025Article
- Microenvironmental dynamics in steady-state and stress erythropoiesis.Blood science (Baltimore, Md.) · 2025Review
- Transcriptional regulators of fetal hemoglobin.Hematology, transfusion and cell therapy · 2024Review
- CRISPR technology in human diseases.MedComm · 2024Review
- CRISPR-Cas9 system: a novel and promising era of genotherapy for beta-hemoglobinopathies, hematological malignancy, and hemophilia.Annals of hematology · 2024Review
- Ex vivo culture resting time impacts transplantation outcomes of genome-edited human hematopoietic stem and progenitor cells in xenograft mouse models.Cytotherapy · 2024Article
- Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- CRISPR/Cas9 Ablated BCL11A Unveils the Genes with Possible Role of Globin Switching.Advanced pharmaceutical bulletin · 2023Article
- The p53 challenge of hematopoietic stem cell gene editing.Molecular therapy. Methods & clinical development · 2023Review
- Efficient non-viral delivery of macromolecules in human primary hematopoietic stem cells and lymphocytes.Journal of molecular cell biology · 2023Article
- An improved medium formulation for efficientMolecular therapy. Methods & clinical development · 2023Article
- Pre-existing immunity does not impair the engraftment of CRISPR-Cas9-edited cells in rhesus macaques conditioned with busulfan or radiation.Molecular therapy. Methods & clinical development · 2023Article
- Identification of non-coding silencer elements and their regulation of gene expression.Nature reviews. Molecular cell biology · 2023Review
- Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies.International journal of molecular sciences · 2023Review
Corrections and comments
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Authors and funding
27 authors at 6 institutions in 2 countries.
Funding
Abstract
Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from patients with sickle cell disease (SCD) induces fetal hemoglobin (HbF) without detectable toxicity, as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer-edited HSPCs in 4 nonhuman primates. We used a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits persisted in peripheral blood (PB) and bone marrow (BM) for up to 101 weeks similarly for BCL11A enhancer- or control locus-targeted (AAVS1-targeted) cells. Biallelic BCL11A enhancer editing resulted in robust γ-globin induction, with the highest levels observed during stress erythropoiesis. Indels were evenly distributed across PB and BM lineages. Off-target edits were not observed. Nonhomologous end-joining repair alleles were enriched in engrafting HSCs. In summary, we found that edited HSCs can persist for at least 101 weeks after transplant and biallelic-edited HSCs provide substantial HbF levels in PB red blood cells, together supporting further clinical translation of this approach.
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