Adenovirus-mediated expression of beta-adrenergic receptor kinase C-terminus reduces intimal hyperplasia and luminal stenosis of arteriovenous polytetrafluoroethylene grafts in pigs.
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.


RESULTS
This study was aimed at evaluating the efficacy and safety of an adenoviral vector (Ad2/betaARKct) encoding the carboxyl terminus of beta-adrenergic receptor kinase (betaARKct) in a pig model of arteriovenous PTFE graft failure. Transduction of the external jugular vein with Ad2/betaARKct (5E9, 5E10, or 5E11 particles per vein) did not result in systemic toxicity, as measured by clinical and pathological assessments. Ad2/betaARKct 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 betaARKct into the jugular vein represents a viable strategy to treat AV graft hemodialysis vascular access failure.
Luo
Zhengyu
Z
Genzyme Corporation, Framingham, Mass 01701-9322, USA.
Akita
Geoffrey Y
GY
Date
Taro
T
Treleaven
Christopher
C
Vincent
Karen A
KA
Woodcock
Denise
D
Cheng
Seng H
SH
Gregory
Richard J
RJ
Jiang
Canwen
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects; D002408:Catheters, Indwelling / Q000009:adverse effects; D004868:Equipment Failure; D005786:Gene Expression Regulation; D006083:Graft Occlusion, Vascular / Q000628:therapy*; D006965:Hyperplasia / Q000628:therapy*; D011138:Polytetrafluoroethylene / Q000627:therapeutic use*; D011943:Receptors, Adrenergic, beta / Q000008:administration & dosage*; D006435:Renal Dialysis; D013552:Swine; D014161:Transduction, Genetic; D017539:Tunica Intima / Q000473:pathology*
D011943:Receptors, Adrenergic, beta; D011138:Polytetrafluoroethylene