Low-efficiency of percutaneous adenovirus-mediated arterial gene transfer in the atherosclerotic rabbit.

Abstract

Recombinant adenoviruses are the most efficient vectors with which to perform arterial gene transfer. Previous in vivo studies of adenovirus-mediated arterial transfection, however, have been performed using normal or endothelium-denuded arteries. It is unclear whether these results can be extended to atherosclerotic arteries. Accordingly, this study was designed to (a) assess the feasibility of adenovirusmediated gene transfer to atherosclerotic lesions, and (b) compare the transfection efficiency, anatomic distribution of transfected cells, and duration of transgene expression achieved in normal versus atherosclerotic arteries. A recombinant adenovirus including a nuclear-targeted (-galactosidase gene was percutaneously delivered to the iliac artery of normal (n = 25) and atherosclerotic (n = 25) rabbits. Transgene expression, assessed by morphometric as well as chemiluminescent analyses, was documented in all normal and atherosclerotic arteries between 3 and 14 d after gene transfer, but was undetectable at later time points. Transfected cells were identified as smooth muscle cells located in the media of normal arteries, and in the neointima and the vasa-vasora of atherosclerotic arteries. Two percent of medial cells, but only 0.2% of medial and neointimal cells expressed the transgene in normal and atherosclerotic arteries, respectively (P = 0.0001). Similarly, nuclear ,B-galactosidase activity was higher in normal than in atherosclerotic arteries (3.2 vs. 0.8 mU/mg protein, P = 0.02). These findings indicate that atherosclerosis reduces the transfection efficiency which can be achieved with adenoviral vectors, and thus constitutes a potential limitation to adenovirus-based, arterial gene therapy. (J. Clin. Invest. 1995. 95:2662-2671

Adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor promotes collateral development in a rabbit model of hind limb ischemia

“…2 In order to develop a therapy to enhance collateral development, these growth factors have been tested in vivo with several delivery techniques. [4][5][6][7] Direct administration of growth factor protein was initially investigated in animal models of ischemia, which showed significant development of collateral vessels and improvement of the ischemic state. 4,5,8 However, high-dose bolus delivery has a high potential risk of systemic toxicity through cytokine diffusion into the systemic circulation.…”

“…transferred into arterial wall cells, 6 or muscle cells 7 of ischemic tissue. Gene therapy directed to arterial wall cells, however, has limitations in the delivery to complicated arterial lesions and efficiency of gene transfer.…”

“…Gene therapy directed to arterial wall cells, however, has limitations in the delivery to complicated arterial lesions and efficiency of gene transfer. 6 Meanwhile, Tsurumi et al 7 transferred the VEGF gene to muscle cells by intramuscular injection of naked DNA, and collateral vessel development was significantly augmented. This method utilized the unique profile of striated muscle cells that potentially take up and express a foreign gene transferred in the form of naked plasmid DNA.…”

Age-related neuronal vulnerability to brain ischemia: A potential target of gene therapy

“…Efficiency of gene transfer to the atherosclerotic vessel is an important issue, because low efficiency was reported in a rabbit's model of angioplasty [28]. Therefore, we examined the efficacy of gene transfer to the endothelium of atherosclerotic vessels using cholesterol-fed monkeys [29].…”

Effect of percutaneous adenovirus-mediated Gax gene delivery to the arterial wall in double-injured atheromatous stented rabbit iliac arteries

“…Other homeobox genes have been shown to function as regulators of cellular differentiation and growth, 7,8 we have shown that overexpression of the Gax gene in normal rat carotid and rabbit iliac arteries can inhibit the fibro-proliferative response to balloon injury, 20,21 an effect that may be mediated by its ability to suppress integrin expression. 22 Adenovirus-mediated gene transfer performed in atheromatous vessels [23][24][25][26][27] combined with stent implantation [28][29][30][31][32][33][34] constitute two important challenges for clinical application. Here, we present the results of percutaneous adenovirus-mediated Gax gene transfer to atheromatous, stented rabbit iliac arteries in a clinical model of balloon angioplasty performed with the channel balloon catheter.…”