ArticleCell stem cell2025
Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.
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Article in Cell stem cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24citing papers in PubMed
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Who cites it
24 citing papers in PubMed.
- Article
- Enhanced γ-globin reactivation and sickle cell correction through a repressor-to-activator motif switch in theMolecular therapy. Nucleic acids · 2026Article
- Article
- Gene editing of hematopoietic stem cells: applications and advances.International journal of hematology · 2026Review
- Monitoring biological effects of somatic cell genome editing.Nature reviews. Genetics · 2026Review
- Next-Generation Metabolic Reprogramming in iPSC-Derived Cardiomyocytes: CRISPR-EV Synergy for Precision Cardiac Regeneration.Biomolecules · 2026Review
- Comparative analysis of CRISPR-Cas9, lentiviral transduction, and base editing for sickle cell disease in a murine model.Blood advances · 2026Article
- Emerging trends in gene and cell therapy: CRISPR in DNA editing and beyond.Cell reports. Medicine · 2026Review
- Single-cell multiplex approaches deeply map ON-target CRISPR-genotoxicity and reveal its mitigation by palbociclib and long-term engraftment.Nature communications · 2026Article
- Developing pineapples with an extended shelf life through deletion of the abscisic-acid-responsive element in the enhancer sequence of the 1-aminocyclopropane-1-carboxylate synthase gene AcoACS1.Frontiers in plant science · 2026Article
- Transduction of Quiescent Human Hematopoietic Stem and Progenitor Cells Using Lentiviral Vectors and Virus-Like Particles.Current protocols · 2026Article
- In situ gene editing of hematopoietic stem cells via AAV-delivered CRISPR guide RNAs.Blood advances · 2025Article
- Gene Therapy of Beta Hemoglobinopathies.Biomedicines · 2025Review
- CRISPR-based therapeutic genome editing for inherited blood disorders.Nature reviews. Drug discovery · 2025Review
- Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease.Cell reports. Medicine · 2025Article
- Peptide-enabled ribonucleoprotein delivery for CRISPR engineering (PERC) in primary human immune cells and hematopoietic stem cells.Nature protocols · 2025Review
- The hidden risks of CRISPR/Cas: structural variations and genome integrity.Nature communications · 2025Review
- Engineering biomimetic bone marrow niche with gene modified mesenchymal stromal cells for ex vivo culture of human hematopoietic stem and progenitor cells.Stem cell research & therapy · 2025Article
- Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.Cell reports. Medicine · 2025Article
- BCL11A-deficient human erythropoiesis is impaired in vitro and after xenotransplantation into mice.Blood advances · 2025Article
Corrections and comments
- Update of
Authors and funding
33 authors.
Jing ZengDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
My Anh NguyenDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Pengpeng LiuDepartment of Molecular, Cell and Cancer Biology, Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Lucas Ferreira da SilvaDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Sébastien LevesqueDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Linda Y LinDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
David G JustusDepartment of Pathology, Harvard Medical School, Boston, MA 02115, USA; Program in Transfusion Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Karl PetriMolecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Kendell ClementMolecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Shaina N PorterDepartment of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Archana VermaDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Nola R NeriDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Tolulope RosanwoDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Marioara-Felicia CiuculescuTransLab, Boston Children's Hospital, Boston, MA 02115, USA.
Daniela AbrissTransLab, Boston Children's Hospital, Boston, MA 02115, USA.
Esther MintzerDepartment of Molecular, Cell and Cancer Biology, Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Stacy A MaitlandDepartment of Molecular, Cell and Cancer Biology, Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Selami DemirciCellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Hye Ji ChaDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Stuart H OrkinDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
John F TisdaleCellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
David A WilliamsDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Lihua Julie ZhuDepartment of Molecular, Cell and Cancer Biology, Department of Molecular Medicine, Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Shondra M Pruett-MillerDepartment of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Luca PinelloMolecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
J Keith JoungMolecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Vikram PattanayakMolecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
John P ManisDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Myriam ArmantTransLab, Boston Children's Hospital, Boston, MA 02115, USA.
Danilo PellinDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Christian BrendelDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Scot A WolfeDepartment of Molecular, Cell and Cancer Biology, Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Daniel E BauerDivision of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bauer@bloodgroup.tch.harvard.edu.
Funding
VIROSOME/PROTEOLIPOSOME MEDIATED GENE TRANSFERP01HL053749 · NHLBI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI RYU, BYOUNG Y · 1994 to 2022
$43.6MCenter for Genomic Editing and Recording: Development and Application of Next-Generation Genome and Epigenome Editing Methods to Advance the Study and Treatment of Human DiseaseRM1HG009490 · NHGRI · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI Brittany S. Adamson, Martin Joseph Ankrah Aryee · 2017 to 2026
$22.7MNovel Strategies to Improve Blood Transfusion PracticeP01HL158688 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI Hongbo R Luo · 2022 to 2026
$12.9MStem Cell and Transplantation BiologyU54DK106829 · NIDDK · FRED HUTCHINSON CANCER RESEARCH CENTER · PI DEREK L STIREWALT · 2015 to 2026
$9.1MEvolution, Optimization, and Application of Genome Editing TechnologiesR35GM118158 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI JOUNG, J. KEITH · 2016 to 2023
$4.7MRectifying splicing mutations in blood disorders by gene editingR01HL150669 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI BAUER, DANIEL EVAN, WOLFE, SCOT A · 2020 to 2023
$3.5MTherapeutic BCL11A enhancer gene editing to induce fetal hemoglobin in β-hemoglobinopathy patientsOT2HL154984 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI BAUER, DANIEL EVAN · 2020 to 2021
$2.6MMultiscale exploration of the functional non-coding genomeR35HG010717 · NHGRI · MASSACHUSETTS GENERAL HOSPITAL · PI PINELLO, LUCA · 2019 to 2023
$2.6MNHGRI NIH HHS R35 HG010717NHGRI NIH HHS RM1 HG009490NHLBI NIH HHS OT2 HL154984NHLBI NIH HHS P01 HL053749NHLBI NIH HHS P01 HL158688NHLBI NIH HHS R01 HL150669NIDDK NIH HHS U54 DK106829NIGMS NIH HHS R35 GM118158
Abstract
Gene editing the BCL11A erythroid enhancer is a validated approach to fetal hemoglobin (HbF) induction for β-hemoglobinopathy therapy, though heterogeneity in edit allele distribution and HbF response may impact its safety and efficacy. Here, we compare combined CRISPR-Cas9 editing of the BCL11A +58 and +55 enhancers with leading gene modification approaches under clinical investigation. Dual targeting of the BCL11A +58 and +55 enhancers with 3xNLS-SpCas9 and two single guide RNAs (sgRNAs) resulted in superior HbF induction, including in sickle cell disease (SCD) patient xenografts, attributable to simultaneous disruption of core half E-box/GATA motifs at both enhancers. Unintended on-target outcomes of double-strand break (DSB) repair in hematopoietic stem and progenitor cells (HSPCs), such as long deletions and centromere-distal chromosome fragment loss, are a byproduct of cellular proliferation stimulated by ex vivo culture. Editing quiescent HSPCs bypasses long deletion and micronuclei formation and preserves efficient on-target editing and engraftment function.
Indexed as
Gene EditingHematopoietic Stem CellsAnemia, Sickle CellAnimalsCRISPR-Cas SystemsFetal HemoglobinHumansMiceRepressor ProteinsBCL11A protein, humanFetal HemoglobinRepressor ProteinsBCL11Aenhancersfetal hemoglobingenotoxicityhematopoietic stem cellssickle cell diseasetherapeutic gene editing
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