Adenovirus-mediated gene transfer to cerebral circulation

Gene therapy may, be a promising approach for treatment of cerebrovascular disease. An adenoviral vector encoding beta-galactosidase was administered intracisternally or intraventricularly into the brain of rats. Efficient ex pression of the reporter gene was observed at the cerebral blood vessels an d perivascular tissues. When the adenoviral vector was delivered into CSF o f dogs suffering from subarachnoid hemorrhage, prominent expressions of tra nsgene were observed. Introduction of the vector to the ischemic brain of r ats provided efficient transgene expression in the peri-ischemic area. Ther efore, gene transfer to the cerebral blood vessel and brain may be a promis ing approach for gene therapy of stroke. Atherosclerotic lesion plays an im portant role in stroke. We evaluated efficacy of adenovirus-mediated gene t ransfer to the atherosclerotic vessels from monkeys and rabbits using an ex vivo gene transfer system. Efficiency of transgene expression in the ather osclerotic endothelium was better than that of normal vessels in both anima ls. Thus, the endothelium of atherosclerotic vessels may be a good target f or gene therapy. Next, we transfected atherosclerotic carotid arteries from rabbits with an adenoviral vector encoding endothelial nitric oxide syntha se (eNOS). After overexpression of eNOS in the atherosclerotic arteries, th e response to acetylcholine was augmented, showing similar relaxation with normal vessels. These results suggest that gene transfer to atherosclerotic vessels improves endothelial function,which may be a new therapeutic appro ach for cerebrovascular disease. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.