ArticleExperimental hematology2008
Tightly regulated gene expression in human hematopoietic stem cells after transduction with helper-dependent Ad5/35 vectors.
Article in Experimental hematology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- Article
- HDAd5/35Molecular therapy. Methods & clinical development · 2018Article
- Integrating HDAd5/35++ Vectors as a New Platform for HSC Gene Therapy of Hemoglobinopathies.Molecular therapy. Methods & clinical development · 2018Article
- In Vivo Hematopoietic Stem Cell Transduction.Hematology/oncology clinics of North America · 2017Review
- The therapeutic landscape of HIV-1 via genome editing.AIDS research and therapy · 2017Review
- Article
- A High-Capacity Adenoviral Hybrid Vector System Utilizing the Hyperactive Sleeping Beauty Transposase SB100X for Enhanced Integration.Molecular therapy. Nucleic acids · 2016Article
- Efficient genome editing in hematopoietic stem cells with helper-dependent Ad5/35 vectors expressing site-specific endonucleases under microRNA regulation.Molecular therapy. Methods & clinical development · 2015Article
- Cellular reprogramming of human peripheral blood cells.Genomics, proteomics & bioinformatics · 2013Review
- Transcriptional control of Flt3 ligand targeted by fluorouracil-induced Egr-1 promoter in hematopoietic damage.Journal of biomedical science · 2009Article
- In vivo gene regulation using tetracycline-regulatable systems.Advanced drug delivery reviews · 2009Review
- A rapid protocol for construction and production of high-capacity adenoviral vectors.Nature protocols · 2009Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
objectiveInducible and transient expression of transcription factors, growth factors, or mitogenic factors can be used to influence proliferation or differentiation of hematopoietic progenitor/stem cells (HSC). Furthermore, transient expression of proteins with site-specific endonuclease activity, potentially, can support targeted integration of exogenous transgenes into specific sites in the genome, a task that is currently a focus in development of gene therapy vectors. MATERIALS AND
methodsWe constructed a set of helper-dependent adenovirus (Ad) vectors with serotype 35 fiber knob domains (HD-Ad5/35), which can efficiently transduce human CD34(+) cells, particularly subsets with potential stem cell capacity. These vectors contain Tet-inducible expression systems that were shielded by insulators and transcription stop signals to minimize unspecific interference by transcriptional elements present in viral and stuffer DNA. We compared two vectors, containing a fusion between the Krüppel-associated box (KRAB) domain and the tetracycline repressor (HD-Ad5/35.Tet-1) or an autoregulated rtTA (HD-Ad5/35.Tet-2) for regulated transgene expression in Mo7e cells, a model for HSC, and primary human CD34(+) cells.
resultsHD-Ad5/35.Tet-1 conferred lower background expression than HD-Ad5/35.Tet-2, although levels of induced gene expression were higher for HD-Ad5/35.Tet-2. In CD34(+) cells, while HD-Ad5/35.Tet-1 allowed for activated gene expression in all transduced cells, induced gene expression from HD-Ad5/35.Tet-2 was restricted to a small subset of CD34(+) cells. Importantly, clonogeneic assays and repopulation studies in nonobese diabetic/severe combined immunodeficient mice showed that both HD-Ad5/35.Tet-1 and -2 vectors mediated induced gene expression in primitive hematopoietic cells. These studies also confirmed that transduction of CD34(+) cells with HD-Ad5/35 vectors is not associated with cytotoxicity, a problem observed with first-generation Ad5/35 vectors.
conclusionsBoth HD-Ad5/35 vector expression systems confer tightly regulated, transient transgene expression in human HSC.
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