Catheter-mediated delivery of adenoviral vectors expressing beta-adrenergic receptor kinase C-terminus inhibits intimal hyperplasia and luminal stenosis in rabbit iliac arteries.
BACKGROUND
Previous studies have shown that incubation of balloon-injured rat carotid arteries with adenoviral vectors encoding the carboxyl terminus of the beta-adrenergic receptor kinase (Ad2/betaARKct) for 30 min reduces neointima formation. However, it is unclear whether this beneficial effect of betaARKct could be achieved using a catheter-based vector delivery system and whether the observed inhibition of neointima formation translated into a reduction of vessel stenosis.


METHODS
In this study, Ad2/betaARKct was infused into the balloon-injured site of rabbit iliac arteries using a porous infusion catheter over 2 min. Twenty-eight days after gene transfer, angiographic and histological assessments were performed.


RESULTS
Angiographic and histological assessments indicate significant (p < 0.05) inhibition of iliac artery neointima formation and lumen stenosis by Ad2/betaARKct. Our studies demonstrate that an inhibitory effect of Ad2/betaARKct on neointima formation is achievable using a catheter-based vector delivery system and that the inhibition of neointima formation translates into a gain in the vessel minimal luminal diameter. The extent of inhibition (35%) was comparable to that observed with adenoviral-mediated expression of thymidine kinase plus ganciclovir treatment, a cytotoxic gene therapy approach for restenosis.


CONCLUSIONS
These results suggest that adenoviral-mediated gene transfer of betaARKct is a clinically viable cytostatic gene therapy strategy for the treatment of restenosis.
Luo
Zhengyu
Z
Genzyme Corporation, Framingham, MA 01701, USA.
Palasis
Maria
M
Yamakawa
Midori
M
Liu
Louis X
LX
Vincent
Karen A
KA
Trudell
Leonard
L
Akita
Geoffrey A
GA
Koch
Walter J
WJ
Cheng
Seng H
SH
Gregory
Richard J
RJ
Jiang
Canwen
C
D000256:Adenoviridae / Q000235:genetics*; D000792:Angiography; D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D003251:Constriction, Pathologic / Q000517:prevention & control / Q000628:therapy*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006965:Hyperplasia / Q000473:pathology / Q000628:therapy*; D007083:Iliac Artery / Q000473:pathology*; D017434:Protein Structure, Tertiary; D011817:Rabbits; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology*; D051552:beta-Adrenergic Receptor Kinases; D001616:beta-Galactosidase / Q000378:metabolism
D017931:DNA Primers; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D001616:beta-Galactosidase