Second-generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall

Details

Serval ID
serval:BIB_2D7C6180A977
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Second-generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall
Journal
Arteriosclerosis, Thrombosis, and Vascular Biology
Author(s)
Wen  S., Schneider  D. B., Driscoll  R. M., Vassalli  G., Sassani  A. B., Dichek  D. A.
ISSN
1079-5642 (Print)
Publication state
Published
Issued date
06/2000
Volume
20
Number
6
Pages
1452-8
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Jun
Abstract
The utility of adenoviral vectors for arterial gene transfer is limited by the brevity of their expression and by inflammatory host responses. As a step toward circumventing these difficulties, we used a rabbit model of in vivo arterial gene transfer to test 3 second-generation vectors: a vector containing a temperature-sensitive mutation in the E2A region, a vector deleted of E2A, and a vector that expresses the immunomodulatory 19-kDa glycoprotein (gp19k) from adenovirus 2. Compared with similar first-generation vectors, the second-generation vectors did not significantly prolong beta-galactosidase transgene expression or decrease inflammation in the artery wall. Although cyclophosphamide ablated the immune and inflammatory responses to adenovirus infusion, it only marginally prolonged transgene expression (94% drop in expression between 3 and 14 days). In experiments performed with "null" adenoviral vectors (no transgene), loss of vector DNA from the arterial wall was also rapid (>99% decrease between 1 hour and 14 days), unrelated to dose, and only marginally blunted by cyclophosphamide. Thus, the early loss of transgene expression after adenoviral arterial gene transfer is due primarily to loss of vector DNA, is not correlated with the presence of local vascular inflammation, and cannot be prevented by use of E2A-defective viruses, expression of gp19k, or cyclophosphamide-mediated immunosuppression. Adenovirus-induced vascular inflammation can be prevented by cyclophosphamide treatment or by lowering the dose of infused virus. However, stabilization of adenovirus-mediated transgene expression in the arterial wall is a more elusive goal and will require novel approaches that prevent the early loss of vector DNA.
Keywords
Adenoviridae/*genetics Animals Arteries/*metabolism Basic Helix-Loop-Helix Transcription Factors Cyclophosphamide/pharmacology DNA/*metabolism *DNA-Binding Proteins *Gene Expression *Gene Transfer Techniques *Genetic Vectors/adverse effects Immunosuppressive Agents/pharmacology Male Rabbits Transcription Factors/genetics Vasculitis/etiology beta-Galactosidase/genetics
Pubmed
Web of science
Create date
28/01/2008 10:32
Last modification date
20/08/2019 13:12
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