© 2000 American Heart Association, Inc.
Vascular Biology |
Second-Generation Adenoviral Vectors Do Not Prevent Rapid Loss of Transgene Expression and Vector DNA From the Arterial Wall
From the Gladstone Institute of Cardiovascular Disease (S.W., D.B.S., R.M.D., G.V., A.B.S., D.A.D.), San Francisco, Calif, and the Department of Medicine and Cardiovascular Research Institute (S.W., D.A.D.), University of California, San Francisco.
Correspondence to Dr David A. Dichek, Gladstone Institute of Cardiovascular Disease/UCSF, PO Box 419100, San Francisco, CA 94141-9100. E-mail ddichek{at}gladstone.ucsf.edu
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 ß-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.
Key Words: rabbits • gene therapy • carotid arteries • ß-galactosidase • inflammation
This article has been cited by other articles:
 |
|
 |
|
  A. S. Narang and R. I. Mahato Biological and biomaterial approaches for improved islet transplantation. Pharmacol. Rev., June 1, 2006; 58(2): 194 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Otsuka, R. Agah, A. D. Frutkin, T. N. Wight, and D. A. Dichek Transforming Growth Factor Beta 1 Induces Neointima Formation Through Plasminogen Activator Inhibitor-1-Dependent Pathways Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 737 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wen, S. Graf, P. G. Massey, and D. A. Dichek Improved Vascular Gene Transfer With a Helper-Dependent Adenoviral Vector Circulation, September 14, 2004; 110(11): 1484 - 1491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Falkenberg, C. Tom, M. B. DeYoung, S. Wen, R. Linnemann, and D. A. Dichek Increased expression of urokinase during atherosclerotic lesion development causes arterial constriction and lumen loss, and accelerates lesion growth PNAS, August 6, 2002; 99(16): 10665 - 10670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wen, R. M. Driscoll, D. B. Schneider, and D. A. Dichek Inclusion of the E3 Region in an Adenoviral Vector Decreases Inflammation and Neointima Formation After Arterial Gene Transfer Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1777 - 1782. [Abstract] [Full Text] [PDF]
|
|