Local Gene Delivery: Arterial Thrombosis Model for Endothelial Cell‐Targeted Thrombolytic Gene Therapy Research

Abstract

The authors describe a rabbit arterial thrombosis model that employs vessel division followed by microsurgical anastomosis and transluminal sutures, to reliably induce thrombus formation in the common femoral artery (CFA). Using two objective measures, "evacuation/refill" evaluation of patency and computer-aided histomorphometric analysis of the thrombus area, thrombus formation was confirmed and characterized in the model at both short- and long-term observation time-points. In addition, a gene delivery method was developed in the CFA that employs an adenoviral vector solution injected through the inferior epigastric artery (IEA). Using this method, a marker transgene (beta-galactosidase) was delivered to endothelial cells locally and without trauma. By subsequently performing beta-galactosidase staining, effective endothelial transfection was demonstrated simultaneously with endothelial viability, with preserved endothelial synthetic function in the immediate environment of the occluding thrombus. The results suggest that these two techniques can be used together in one model, to effectively introduce a foreign therapeutic transgene into endothelial cells and to evaluate the effect of the expressed protein product in a consistent in vivo thrombosis system. This combined model may be used as one of several assays of efficacy in future endothelial cell-targeted thrombolytic/antithrombotic vascular gene therapy research.

Gene Therapy and Endovascular Treatment of Intracranial Aneurysms

“…For example, to prevent thrombosis in nondenuded vessels, endothelial cells are the target. 45 Conversely, medial smooth muscle cells may be targeted to prevent restenosis after balloon angioplasty. 46 The endothelial lining is a biological barrier to viral vectors; angioplasty leads to denudation of the arterial wall, permitting viral vectors to reach smooth muscle cells effectively.…”

Neue antithrombotische Therapieansätze bei koronarer Herzerkrankung – Perspektiven einer Gentherapie

“…Die durch eine Verletzung eingeschränkte endotheliale Prostzyklinsynthese bedingt eine lokale Aktivierung von Thrombozyten mit konsekutiver Adhäsion und Aggregation. (TFPI= tissue factor pathway inhibitor; COX-1 = cyclooxygenase-1; t-PA= tissue-type-Plasminogen-Aktivator) tomosen untersucht (69). In der Adaption für eine gentherapeutische Studie wurde nach der Durchtrennung der A. femoralis communis diese mikrochirurgisch reanastomisiert und das wiederhergestellte Gefäß mittels Adenoviren transduziert.…”