Source:http://linkedlifedata.com/resource/pubmed/id/10646643
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions |
umls-concept:C0001483,
umls-concept:C0003595,
umls-concept:C0017262,
umls-concept:C0021920,
umls-concept:C0035820,
umls-concept:C0085201,
umls-concept:C0086222,
umls-concept:C0086418,
umls-concept:C0086860,
umls-concept:C0185117,
umls-concept:C1517499,
umls-concept:C1521751,
umls-concept:C1547239,
umls-concept:C1677784,
umls-concept:C1705733,
umls-concept:C2911684
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| pubmed:issue |
1
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| pubmed:dateCreated |
2000-2-11
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| pubmed:abstractText |
Elevation of HDL cholesterol, after adenoviral apolipoprotein A-I (apo A-I) gene transfer, may delay or revert ischemic cardiovascular disease, provided transgene expression is persistent. Previously, we observed transient human apo A-I expression after adenoviral gene transfer with a cytomegalovirus (CMV)-driven construct containing the human apo A-I cDNA. Therefore, the effects of promoters (CMV or 256 base pairs of the human apo A-I promoter), introns of the human apo A-I gene, and the liver-specific human apolipoprotein E (apo E) enhancer on adenovirus-mediated human apo A-I expression were evaluated in C57BL/6 mice. In the presence of the CMV promoter, human apo A-I introns prolonged expression above 20 mg/dl from 14 to 35 days. Addition of one, two, or four copies of the human apo E enhancer in these constructs resulted in a copy-dependent but transient increase in expression for 14 days. The apo A-I promoter induced 3.2-fold lower peak levels of human apo A-I than did the CMV promoter, but insertion of four apo E enhancers in the apo A-I promoter-driven construct resulted in human apo A-I levels above 20 mg/dl for 6 months. The decline between day 6 and day 35 of human apo A-I expression driven by the CMV promoter was due to (1) a 2.5-fold decline in transgene DNA levels that is not observed with apo A-I promoter-driven constructs, and (2) CMV promoter attenuation as evidenced by a 7.6-fold decline in the human apo A-I mRNA/human apo A-I DNA copy number ratio between day 6 and day 35. Hepatotoxicity, as evidenced by up to 10-fold higher serum levels of transaminases on day 6 after gene transfer with CMV promoter-driven constructs than with apo A-I promoter-driven constructs, probably caused the accelerated decline of transgene DNA. In conclusion, gene transfer with an adenovirus comprising the 256-bp apo A-I promoter, the genomic apo A-I DNA, and four apo E enhancers, all of human origin, is associated with low hepatotoxicity and with the absence of promoter shutoff resulting in human apo A-I expression above 20 mg/dl for up to 6 months.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Jan
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| pubmed:issn |
1043-0342
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
1
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| pubmed:volume |
11
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
101-12
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| pubmed:dateRevised |
2008-11-21
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| pubmed:meshHeading |
pubmed-meshheading:10646643-Adenoviridae,
pubmed-meshheading:10646643-Animals,
pubmed-meshheading:10646643-Apolipoprotein A-I,
pubmed-meshheading:10646643-Apolipoproteins E,
pubmed-meshheading:10646643-Base Sequence,
pubmed-meshheading:10646643-Cell Division,
pubmed-meshheading:10646643-DNA Primers,
pubmed-meshheading:10646643-Enhancer Elements, Genetic,
pubmed-meshheading:10646643-Female,
pubmed-meshheading:10646643-Gene Transfer Techniques,
pubmed-meshheading:10646643-Genetic Vectors,
pubmed-meshheading:10646643-Humans,
pubmed-meshheading:10646643-Introns,
pubmed-meshheading:10646643-Liver,
pubmed-meshheading:10646643-Mice,
pubmed-meshheading:10646643-Mice, Inbred C57BL,
pubmed-meshheading:10646643-Promoter Regions, Genetic,
pubmed-meshheading:10646643-Recombination, Genetic,
pubmed-meshheading:10646643-T-Lymphocytes
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| pubmed:year |
2000
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| pubmed:articleTitle |
Sustained expression of human apolipoprotein A-I after adenoviral gene transfer in C57BL/6 mice: role of apolipoprotein A-I promoter, apolipoprotein A-I introns, and human apolipoprotein E enhancer.
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| pubmed:affiliation |
Center for Molecular and Vascular Biology, Leuven, Belgium.
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| pubmed:publicationType |
Journal Article
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