| Multiply deleted [E1, polymerase-, and pTP-] adenovirus vector persists despite deletion of the preterminal protein. | |
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MedLine Citation:
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PMID: 10953916 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: The inherent limitations of [E1-]Ad vectors as gene therapy vehicles suggest that further modifications may improve their overall performance profiles. However, Ad vector modifications can have untoward effects on their basic biology, e.g., some helper-virus dependent Ad vectors have been found to be unstable without the presence of preterminal protein (pTP) activities. Despite this concern, we generated a new class of helper-virus independent Ad vector that was multiply deleted for the E1, polymerase, and pTP genes, and investigated the ramifications of these deletions upon several vector performance parameters. METHODS: The construction and propagation of an [E1-, polymerase-, pTP-]Ad vector was achieved with the use of trans-complementing cells co-expressing the Ad E1, polymerase and pTP genes. RESULTS: High titer production of the [E1-, polymerase-, pTP-]Ad vector was successfully accomplished via conventional Ad purification techniques. This unique class of Ad vector was capable of long-term gene transfer in vivo (despite lacking pTP functions) that was concomitant with a significantly decreased hepatic toxicity. CONCLUSIONS: Previous studies had suggested that Ad genome persistence in vivo may be dependent upon the presence of low level vector genome replication and/or pTP functions. Our results suggest that [E1-, polymerase-, pTP-]Ad vectors can overcome these barriers. The further benefits afforded by the use of this class of Ad vector (increased cloning capacity, high level growth, decreased propensity to generate replication competent Ad (RCA), decreased toxicity) suggests that they will be highly beneficial for use in several aspects of human gene therapy. |
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Authors:
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B L Hodges; D Serra; H Hu; C A Begy; J S Chamberlain; A Amalfitano |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The journal of gene medicine Volume: 2 ISSN: 1099-498X ISO Abbreviation: J Gene Med Publication Date: 2000 Jul-Aug |
Date Detail:
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Created Date: 2000-11-15 Completed Date: 2001-02-22 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9815764 Medline TA: J Gene Med Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 250-9 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae
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genetics* Adenovirus E1 Proteins / genetics Animals Cell Line DNA-Directed DNA Polymerase / genetics Gene Deletion* Gene Transfer Techniques* Genetic Vectors Genome, Viral* Helper Viruses / genetics Humans Mice Mice, Inbred C57BL Mice, SCID Phosphoproteins / genetics* Protein Precursors / genetics* Transduction, Genetic Viral Proteins / genetics* |
| Grant Support | |
ID/Acronym/Agency:
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R01-DK 52925-01/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adenovirus E1 Proteins; 0/Phosphoproteins; 0/Protein Precursors; 0/Viral Proteins; 0/pTP protein, adenovirus; EC 2.7.7.7/DNA-Directed DNA Polymerase |
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