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Attenuation Of Neointimal Thickening By Adenoviral Mediated Gene Transfer Of Retinoblastoma Protein

Amito Chandiwal, James Vosciky, Lewis Schwartz, Christopher Skelly ∙ University of Chicago, Chicago, IL

Objectives: Adenovirus-mediated arterial gene transfer is a promising tool in the study of vessel biology and the development of vascular gene therapy. Restenosis due to excessive vascular smooth muscle cell proliferation in excess of apoptosis remains the major cause of vessel occlusion following percutaneous interventions. Various strategies including, intervention with pharmacologic or biologic agents, in an attempt to modulate this response have been studied with limited success. The purpose of this study was to test the hypothesis that a replication deficient adenovirus encoding a constitutively active form of the retinoblastoma protein (AdDeltaRb) would attenuate neointimal thickening in an animal model of arterial restenosis. Methods: Using standard aseptic techniques, the left common carotid artery (CCA) of 9 NZ White Rabbits was exposed and clamped. Injury was created using 3 passes of a 3F balloon catheter and CCA was then exposed intraluminally either to vehicle (PBS) in controls or AdDeltaRb (1x1010 pfu/ml) in the treated groups. The CCA was then restricted by ligating over a 0.014 guide wire distal to the cranial thyroid branch and the arteriotomy repaired. For the sham group the left CCA was temporally exposed and sutured closed as the others. Animals received aspirin and clopidogrel for the duration of survival. At 4 weeks the arteries were perfusion-fixed and histomorphometry performed after staining with WVG. Results: All arteries were patent at sacrifice. There was more than 2 fold decrease in NIT and greater than 1.5 fold decrease in the medial and total wall thickness in the AdDeltaRb treated group as compared to the control. (Fig.1). Conclusions: Intraluminal exposure of the CCA to AdDeltaRb resulted in a decrease in NIT compared to control. The retinoblastoma protein functions as a tumor suppressor gene and is a key modulator of cell cycle transit and controls cell division. Incorporation of this protein into an adenovirus vector might be an efficient approach to prevent neointima formation in arterial restenosis through inhibition of vascular smooth muscle cell proliferation.