| Characteristics of lentiviral vectors harboring the proximal promoter of the vav proto-oncogene: a weak and efficient promoter for gene therapy. | |
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MedLine Citation:
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PMID: 17534266 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Recent published data have shown the efficacy of gene therapy treatments of certain monogenic diseases. Risks of insertional oncogenesis, however, indicate the necessity of developing new vectors with weaker or cell-restricted promoters to minimize the trans-activation activity of integrated proviruses. We have inserted the proximal promoter of the vav proto-oncogene into self-inactivating lentiviral vectors (vav-LVs) and investigated the expression pattern and therapeutic efficacy of these vectors. Compared with other LVs frequently used in gene therapy, vav-LVs mediated a weak, though homogeneous and stable, expression in in vitro-cultured cells. Transplantation experiments using transduced mouse bone marrow and human CD34(+) cells confirmed the stable activity of the promoter in vivo. To investigate whether the weak activity of this promoter was compatible with a therapeutic effect, a LV expressing the Fanconi anemia A (FANCA) gene was constructed (vav-FANCA LV). Although this vector induced a low expression of FANCA, compared to the expression induced by a LV harboring the spleen focus-forming virus (SFFV) promoter, the two vectors corrected the phenotype of cells from a patient with FA-A with the same efficacy. We propose that self-inactivating vectors harboring weak promoters, such as the vav promoter, will improve the safety of gene therapy and will be of particular interest for the treatment of diseases where a high expression of the transgene is not required. |
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Authors:
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Elena Almarza; Paula Río; Nestor W Meza; Montserrat Aldea; Xabier Agirre; Guillermo Guenechea; José C Segovia; Juan A Bueren |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-05-29 |
Journal Detail:
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Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: 15 ISSN: 1525-0016 ISO Abbreviation: Mol. Ther. Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-07-24 Completed Date: 2007-09-26 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 1487-94 Citation Subset: IM |
Affiliation:
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Hematopoiesis and Gene Therapy Division, CIEMAT/CIBER-ER and Marcelino Botín Foundation, Madrid, Spain. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Base Sequence Cells, Cultured DNA Methylation Fanconi Anemia Complementation Group A Protein / genetics, metabolism Gene Expression Gene Expression Regulation Gene Therapy* Gene Transfer Techniques Genetic Vectors / genetics* Humans Lentivirus / genetics* Mice Phenotype Promoter Regions, Genetic / genetics* Proto-Oncogene Proteins c-vav / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Fanconi Anemia Complementation Group A Protein; 0/Proto-Oncogene Proteins c-vav |
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