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(Circulation. 2005;111:1679-1684.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Adenovirus-Mediated Expression of ß-Adrenergic Receptor Kinase C-Terminus Reduces Intimal Hyperplasia and Luminal Stenosis of Arteriovenous Polytetrafluoroethylene Grafts in Pigs

Zhengyu Luo, MD; Geoffrey Y. Akita, DVM, PhD; Taro Date, MD, PhD; Christopher Treleaven, BSc; Karen A. Vincent, PhD; Denise Woodcock, AS; Seng H. Cheng, PhD; Richard J. Gregory, PhD; Canwen Jiang, MD, PhD

From Genzyme Corporation, Framingham, Mass.

Correspondence to Canwen Jiang, MD, PhD, Genzyme Corporation, 31 New York Ave, Framingham, MA 01701-9322. E-mail canwen.jiang{at}genzyme.com

Received September 21, 2004; revision received November 16, 2004; accepted November 19, 2004.

Background— Hemodialysis vascular access dysfunction is the single most important cause of morbidity in kidney hemodialysis patients. Failure of an arteriovenous polytetrafluoroethylene (PTFE) graft, the most common form of hemodialysis access, is primarily due to intimal hyperplasia and thrombosis at the venous anastomosis.

Methods and Results— This study was aimed at evaluating the efficacy and safety of an adenoviral vector (Ad2/ßARKct) encoding the carboxyl terminus of ß-adrenergic receptor kinase (ßARKct) in a pig model of arteriovenous PTFE graft failure. Transduction of the external jugular vein with Ad2/ßARKct (5E9, 5E10, or 5E11 particles per vein) did not result in systemic toxicity, as measured by clinical and pathological assessments. Ad2/ßARKct significantly reduced neointimal hyperplasia in the graft/vein anastomosis. It also improved the graft patency rate and angiographic score, as measured histologically and angiographically, compared with vehicle or empty viral vector controls.

Conclusions— Our results suggest that local administration of adenoviral vectors encoding ßARKct into the jugular vein represents a viable strategy to treat AV graft hemodialysis vascular access failure.

Key Words: thrombosis • hyperplasia • grafting • hemodialysis • gene therapy

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