ArticleBlood2006
Proteasome activity restricts lentiviral gene transfer into hematopoietic stem cells and is down-regulated by cytokines that enhance transduction.
Article in Blood, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 74 citations in OpenAlex.
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- Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes.Nature communications · 2025Article
- Stbd1 promotes glycogen clustering during endoplasmic reticulum stress and supports survival of mouse myoblasts.Journal of cell science · 2020Article
- Review
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- Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives.EMBO molecular medicine · 2019Review
- Gene Therapy For Beta-Thalassemia: Updated Perspectives.The application of clinical genetics · 2019Article
- UM171 Enhances Lentiviral Gene Transfer and Recovery of Primitive Human Hematopoietic Cells.Molecular therapy. Methods & clinical development · 2018Article
- Prostaglandin EMolecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- Ectopic FOXP3 Expression Preserves Primitive Features Of Human Hematopoietic Stem Cells While Impairing Functional T Cell Differentiation.Scientific reports · 2017Article
- Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned.Cell stem cell · 2017Review
- Engineering Stem Cells for Biomedical Applications.Advanced healthcare materials · 2016Review
- Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells.Current opinion in hematology · 2015Review
- Liver-directed lentiviral gene therapy in a dog model of hemophilia B.Science translational medicine · 2015Article
- High-throughput screening identifies compounds that enhance lentiviral transduction.Gene therapy · 2014Article
- Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells.Blood · 2014Article
- Variable correction of Artemis deficiency by I-Sce1-meganuclease-assisted homologous recombination in murine hematopoietic stem cells.Gene therapy · 2014Article
- Non-integrating gamma-retroviral vectors as a versatile tool for transient zinc-finger nuclease delivery.Scientific reports · 2014Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The therapeutic potential of hematopoietic stem cell (HSC) gene therapy can be fully exploited only by reaching efficient gene transfer into HSCs without compromising their biologic properties. Although HSCs can be transduced by HIV-derived lentiviral vectors (LVs) in short ex vivo culture, they display low permissivity to the vector, requiring cytokine stimulation to reach high-frequency transduction. Using stringent assays of competitive xenograft repopulation, we show that early-acting cytokines synergistically enhanced human HSC gene transfer by LVs without impairing engraftment and repopulation capacity. Using S-phase suicide assays, we show that transduction enhancement by cytokines was not dependent on cell cycle progression and that LVs can transduce quiescent HSCs. Pharmacologic inhibition of the proteasome during transduction dramatically enhanced HSC gene transfer, allowing the reach of very high levels of vector integration in their progeny in vivo. Thus, LVs are effectively restricted at a postentry step by the activity of this proteolytic complex. Unexpectedly, cytokine stimulation rapidly and substantially down-regulated proteasome activity in hematopoietic progenitors, highlighting one mechanism by which cytokines may enhance permissiveness to LV gene transfer. These findings demonstrate that antiviral responses ultimately mediated by proteasomes strongly limit the efficiency of HSC transduction by LVs and establish improved conditions for HSC-based gene therapy.
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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.