title: Helper-dependent adenoviral vector achieves prolonged, stable expression of interleukin-10 in rabbit carotid arteries but does not limit early atherogenesis.
abstract: Vascular gene therapy could potentially complement or replace current therapies for human atherosclerosis, while avoiding their side effects. However, development of vascular gene therapy is limited by lack of a useful vector. Helper-dependent adenovirus (HDAd) shows promise to overcome this barrier because, unlike first-generation adenovirus, HDAd achieves durable transgene expression in the artery wall with minimal inflammation. To begin to test whether HDAd, delivered to the artery wall, can limit atherosclerosis we constructed HDAd that expresses rabbit interleukin (IL)-10, a potent atheroprotective cytokine, and tested its activity in a rabbit model of early carotid atherogenesis. HDAd expressed immunoreactive, active IL-10 in vitro. In contrast to other HDAd-expressed transgenes, IL-10 expression from HDAd increased significantly between 3 days and 2 weeks after infusion and remained stable for at least 8 weeks. Rising, persistent IL-10 expression was associated with relative persistence of HDAdIL-10 genomes 4 weeks after infusion, compared with HDAdNull genomes. Surprisingly, IL-10 expression had no significant effects on atherosclerotic lesion size, macrophage content, or expression of either adhesion molecules or atherogenic cytokines. These results might be due to inadequate protein expression in vivo or lack of suitability of this rabbit model to reveal IL-10 therapeutic effects. IL-10 remains a promising agent for vascular gene therapy and HDAd remains a promising vector; however, proof of efficacy of HDAdIL-10 is elusive. Future preclinical studies will be aimed at increasing IL-10 expression levels and improving the sensitivity of this animal model to detect atheroprotective effects.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Du
authors.forename: Nagadhara
authors.initials: N
authors.lastname: Dronadula
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: David A
authors.initials: DA
authors.lastname: Dichek
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D011817:Rabbits
chemical_list: D016753:Interleukin-10