Efficient gene transfer and durable transgene expression in grafted rabbit veins.

Abstract

Venous bypass grafts are useful treatments for obstructive coronary artery disease. However, their usefulness is limited by accelerated atherosclerosis. Genetic engineering of venous bypass grafts that prevented atherosclerosis could improve long-term graft patency and clinical outcomes. We used a rabbit model of jugular vein-to-carotid interposition grafting to develop gene therapy for vein-graft atherosclerosis. Rabbit veins were easily transduced in situ with a first-generation adenoviral vector; however, most transgene expression (∼80%) was lost within 3 days after arterial grafting. This rapid loss of transgene expression was not prevented by transducing veins after grafting or by prolonged ex vivo transduction. However, delaying vein-graft transduction for 28 days (after the vein had adapted to the arterial circulation) prevented this early loss of transgene expression. We used the delayed transduction approach to test the durability of expression of a therapeutic transgene (apolipoprotein A-I) expressed from a helper-dependent adenoviral (HDAd) vector. HDAd DNA and apolipoprotein A-I mRNA were easily detectable in transduced vein grafts. Vector DNA and mRNA declined by 4 weeks, and then persisted stably for at least 6 months. Delaying transduction for 28 days after grafting permitted initiation of vein-graft neointimal growth and medial thickening before gene transfer. However, vein-graft lumen diameter was not compromised, because of gradual outward remodeling of grafted veins. Our data highlight the promise of HDAd-mediated gene therapy, delivered to arterialized vein grafts, for preventing vein-graft atherosclerosis.