ArticleMolecular therapy : the journal of the American Society of Gene Therapy2015
miRNA-embedded shRNAs for Lineage-specific BCL11A Knockdown and Hemoglobin F Induction.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 119 citations in OpenAlex.
- 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
- X-linked SEPTIN6-related congenital neutropenia and B cell deficiency.Journal of human immunity · 2026Article
- shRNAI: A deep neural network for the design of highly potent shRNAs.Molecular therapy. Nucleic acids · 2025Article
- Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease.Cell reports. Medicine · 2025Article
- 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
- Large-scale discovery of potent, compact and erythroid specific enhancers for gene therapy vectors.Nature communications · 2025Article
- Multiplex engineering using microRNA-mediated gene silencing in CAR T cells.Frontiers in immunology · 2025Article
- Suppression of toxic transgene expression by optimized artificial miRNAs increases AAV vector yields in HEK-293 cells.Molecular therapy. Methods & clinical development · 2024Article
- A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease.Molecular therapy. Methods & clinical development · 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
- Transcriptional Repressor BCL11A in Erythroid Cells.Advances in experimental medicine and biology · 2024Review
- Evaluation of Mono- and Bi-Functional GLOBE-Based Vectors for Therapy of β-Thalassemia byCells · 2023Article
- CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia.Human genetics · 2023Review
- Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies.Molecular therapy. Nucleic acids · 2023Article
- Review
- Diverse Approaches to Gene Therapy of Sickle Cell Disease.Annual review of medicine · 2023Review
- Review
- The Novel Role of the B-Cell Lymphoma/Leukemia 11A (BCL11A) Gene in β-Thalassaemia Treatment.Cardiovascular & hematological disorders drug targets · 2023Review
- Effective therapies for sickle cell disease: are we there yet?Trends in genetics : TIG · 2022Review
14 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 8 institutions in 2 countries.
Funding
Abstract
RNA interference (RNAi) technology using short hairpin RNAs (shRNAs) expressed via RNA polymerase (pol) III promoters has been widely exploited to modulate gene expression in a variety of mammalian cell types. For certain applications, such as lineage-specific knockdown, embedding targeting sequences into pol II-driven microRNA (miRNA) architecture is required. Here, using the potential therapeutic target BCL11A, we demonstrate that pol III-driven shRNAs lead to significantly increased knockdown but also increased cytotoxcity in comparison to pol II-driven miRNA adapted shRNAs (shRNA(miR)) in multiple hematopoietic cell lines. We show that the two expression systems yield mature guide strand sequences that differ by a 4 bp shift. This results in alternate seed sequences and consequently influences the efficacy of target gene knockdown. Incorporating a corresponding 4 bp shift into the guide strand of shRNA(miR)s resulted in improved knockdown efficiency of BCL11A. This was associated with a significant de-repression of the hemoglobin target of BCL11A, human γ-globin or the murine homolog Hbb-y. Our results suggest the requirement for optimization of shRNA sequences upon incorporation into a miRNA backbone. These findings have important implications in future design of shRNA(miR)s for RNAi-based therapy in hemoglobinopathies and other diseases requiring lineage-specific expression of gene silencing sequences.
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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.