title: Inhibition of neointimal hyperplasia in a rabbit vein graft model following non-viral transfection with human iNOS cDNA.
abstract: Vein graft failure caused by neointimal hyperplasia (IH) after coronary artery bypass grafting with saphenous veins is a major clinical problem. The lack of safe and efficient vectors for vascular gene transfer has significantly hindered progress in this field. We have developed a Receptor-Targeted Nanocomplex (RTN) vector system for this purpose and assessed its therapeutic efficacy in a rabbit vein graft model of bypass grafting. Adventitial delivery of β-Galactosidase showed widespread transfection throughout the vein wall on day 7, estimated at about 10% of cells in the adventitia and media. Vein grafts were then transfected with a plasmid encoding inducible nitric oxide synthase (iNOS) and engrafted into the carotid artery. Fluorescent immunohistochemistry analysis of samples from rabbits killed at 7 days after surgery showed that mostly endothelial cells and macrophages were transfected. Morphometric analysis of vein graft samples from the 28-day groups showed approximately a 50% reduction of neointimal thickness and 64% reduction of neointimal area in the iNOS-treated group compared with the surgery control groups. This study demonstrates efficacy of iNOS gene delivery by the RTN formulation in reducing IH in the rabbit model of vein graft disease.
authors: Molecular Immunology Unit, UCL Institute of Child Health, University College London, London, UK.
authors: Q-H
authors: QH
authors: Meng
authors: S
authors: S
authors: Irvine
authors: A D
authors: AD
authors: Tagalakis
authors: R J
authors: RJ
authors: McAnulty
authors: J R
authors: JR
authors: McEwan
authors: S L
authors: SL
authors: Hart
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology* / Q000601:surgery; D018076:DNA, Complementary / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000517:prevention & control; D007601:Jugular Veins / Q000637:transplantation*; D008297:Male; D023421:Models, Animal; D058426:Neointima / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D011817:Rabbits; D014162:Transfection
chemical_list: D018076:DNA, Complementary; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
references: Hum Gene Ther. 2003 Mar 1;14(4):375-83
references: 12659678
references: Ann Thorac Surg. 1998 Dec;66(6):1948-52
references: 9930474
references: Lancet. 2000 Jan 15;355(9199):213-22
references: 10675133
references: Circulation. 1998 Nov 3;98(18):1905-11
references: 9799212
references: Science. 1996 Jul 12;273(5272):242-5
references: 8662508
references: Mol Ther. 2008 Nov;16(11):1798-804
references: 18781142
references: Curr Cardiol Rep. 2000 Jan;2(1):29-33
references: 10980869
references: N Engl J Med. 2009 Mar 5;360(10):961-72
references: 19228612
references: Hum Gene Ther. 2006 Jul;17(7):717-27
references: 16839271
references: Circulation. 1999 Jun 29;99(25):3241-7
references: 10385497
references: J Thorac Cardiovasc Surg. 1998 Jan;115(1):152-61
references: 9451059
references: Circulation. 2011 Sep 13;124(11 Suppl):S135-42
references: 21911803
references: Gene Ther. 2005 Jul;12(14):1154-7
references: 15829995
references: Annu Rev Immunol. 2002;20:709-60
references: 11861616
references: Gene Ther. 2012 Jun;19(6):630-6
references: 22456326
references: J Pharm Pharmacol. 2008 Aug;60(8):999-1017
references: 18644193
references: Gene Ther. 1999 Jan;6(1):6-11
references: 10341870
references: Circ Res. 2006 Feb 17;98(3):412-20
references: 16385078
references: Circulation. 2001 Sep 25;104(13):1526-32
references: 11571247
references: Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H1865-72
references: 16219811
references: Expert Opin Drug Deliv. 2012 Feb;9(2):249-65
references: 22235930
references: Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H240-5
references: 14500133
references: Circulation. 1997 Jun 17;95(12):2684-93
references: 9193438
references: Br Heart J. 1994 Apr;71(4):382-5
references: 8198893
references: J Surg Res. 2010 Jun 1;161(1):162-7
references: 19361808
references: Circulation. 1998 Mar 10;97(9):916-31
references: 9521341
references: J Clin Invest. 2004 May;113(9):1258-65
references: 15124016
references: Trends Cardiovasc Med. 2004 Oct;14(7):267-72
references: 15542378
references: Hum Gene Ther. 1997 Sep 20;8(14):1645-50
references: 9322866
references: J Vasc Surg. 2001 Jul;34(1):156-65
references: 11436090
references: J Clin Invest. 1995 Dec;96(6):2955-65
references: 8675667
references: J Gene Med. 2002 Jul-Aug;4(4):438-46
references: 12124986
references: Mol Ther. 2008 Mar;16(3):508-15
references: 18180778
references: Circ Res. 1994 Oct;75(4):650-8
references: 7923611
references: Arterioscler Thromb Vasc Biol. 2011 Jul;31(7):1530-9
references: 21677296
references: J Am Coll Cardiol. 1990 Jun;15(7):1667-87
references: 2188991
references: Lancet. 1999 Oct 30;354(9189):1493-8
references: 10551494
references: Circ Res. 1998 Jun 29;82(12):1253-62
references: 9648721
references: Mol Ther. 2007 Jul;15(7):1233-47
references: 17505481
references: J Mol Cell Cardiol. 2011 Feb;50(2):304-11
references: 20850452
references: Hum Gene Ther. 2011 Aug;22(8):951-8
references: 21083499