ArticleThe Journal of clinical investigation2016
Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
89 citing papers in PubMed, 160 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
- Post-Transcriptional Genetic Silencing ofThe New England journal of medicine · 2021Trial
- Systemic delivery of phagocytosis-shielded retroviral vectors enables in vivo HSC gene therapy for sickle cell disease.Cell stem cell · 2026Article
- Engineering the Universal Donor: CRISPR-Mediated Blood Group Antigen Deletion and the Path Toward Truly Universal Red Blood Cells-A Narrative Review.Diagnostics (Basel, Switzerland) · 2026Review
- The Molecular Pathology of Non-Malignant Haematological Disease.British journal of biomedical science · 2026Review
- Genetic Engineering in Hematopoietic Stem Cells for β-Hemoglobinopathies Treatment: Advances, Challenges, and Clinical Translation.International journal of hematology-oncology and stem cell research · 2025Review
- Epigenetic Regulation of Erythropoiesis: From Developmental Programs to Therapeutic Targets.International journal of molecular sciences · 2025Review
- BCL11A-deficient human erythropoiesis is impaired in vitro and after xenotransplantation into mice.Blood advances · 2025Article
- Large-scale discovery of potent, compact and erythroid specific enhancers for gene therapy vectors.Nature communications · 2025Article
- Ex vivo modification of hematopoietic stem and progenitor cells for gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.Cell stem cell · 2025Article
- Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia.Cell stem cell · 2025Article
- Upregulation of miR‑6747‑3p affects red blood cell lineage development and induces fetal hemoglobin expression by targeting BCL11A in β‑thalassemia.Molecular medicine reports · 2025Article
- Review
- A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing.Science (New York, N.Y.) · 2024Article
- UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease.Blood advances · 2024Article
- Article
- A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease.Molecular therapy. Methods & clinical development · 2024Article
- Interplay between α-thalassemia and β-hemoglobinopathies: Translating genotype-phenotype relationships into therapies.HemaSphere · 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
29 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 6 institutions in 2 countries.
Funding
Abstract
Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia. Here, we found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities. BCL11A knockdown was associated with a substantial increase in S/G2-phase human HSCs after engraftment into immunodeficient (NSG) mice, a phenotype that is associated with HSC exhaustion. Lineage-specific, shRNAmiR-mediated suppression of BCL11A in erythroid cells led to stable long-term engraftment of gene-modified cells. Transduced primary normal or SCD human HSCs expressing the lineage-specific BCL11A shRNAmiR gave rise to erythroid cells with up to 90% reduction of BCL11A protein. These erythrocytes demonstrated 60%-70% γ-chain expression (vs. < 10% for negative control) and a corresponding increase in HbF. Transplantation of gene-modified murine HSCs from Berkeley sickle cell mice led to a substantial improvement of sickle-associated hemolytic anemia and reticulocytosis, key pathophysiological biomarkers of SCD. These data form the basis for a clinical trial application for treating sickle cell disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.