title: Helper-dependent adenoviral vectors are superior in vitro to first-generation vectors for endothelial cell-targeted gene therapy.
abstract: Arterial endothelial cells (EC) are attractive targets for gene therapy of atherosclerosis because they are accessible to hematogenous and catheter-based vector delivery and overlie atherosclerotic plaques. Vector-mediated expression-in EC-of proteins that mediate cholesterol transfer out of the artery wall and decrease inflammation could prevent and reverse atherosclerosis. However, clinical application of this strategy is limited by lack of a suitable gene-transfer vector. First-generation adenovirus (FGAd) is useful for EC gene transfer in proof-of-concept studies, but is unsuitable for atheroprotective human gene therapy because of limited duration of expression and proinflammatory effects. Moreover, others have reported detrimental effects of FGAd on critical aspects of EC physiology including proliferation, migration, and apoptosis. Here, we investigated whether helper-dependent adenovirus (HDAd) either alone or expressing an atheroprotective gene [apolipoprotein A-I (apoA-I)] could circumvent these limitations. In contrast to control FGAd, HDAd did not alter any of several critical EC physiologic functions (including proliferation, migration, apoptosis, metabolic activity, and nitric oxide (NO) production) and did not stimulate proinflammatory pathways [including expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and interleukin-6 (IL-6)]. Expression of apoA-I by HDAd reduced EC VCAM-1 expression. HDAd is a promising vector and apoA-I is a promising gene for atheroprotective human gene therapy delivered via EC.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Rowan
authors.initials: R
authors.lastname: Flynn
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Buckler
authors.forename: Chongren
authors.initials: C
authors.lastname: Tang
authors.forename: Francis
authors.initials: F
authors.lastname: Kim
authors.forename: David A
authors.initials: DA
authors.lastname: Dichek
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016632:Apolipoprotein A-I; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; D009569:Nitric Oxide
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