Intravenous delivery of adeno-associated viral vector serotype 9 mediates effective gene expression in ischemic stroke lesion and brain angiogenic foci

摘要

Background and Purpose-: Adeno-associated viral vector (AAV) is a powerful tool for delivering genes to treat brain diseases. Intravenous delivery of a self-complementary but not single-stranded AAV9 (ssAAV9) mediates robust gene expression in the adult brain. We tested if ssAAV9 effectively mediates gene expression in the ischemic stroke lesion and angiogenic foci. Methods-: Focal ischemic stroke was induced by permanent occlusion of the left middle cerebral artery (MCAO) and focal angiogenesis was induced by injecting an AAV expressing vascular endothelial growth factor (AAV-VEGF) into the basal ganglia. ssAAV vectors that have cytomegalovirus (CMV) promoter driving (AAV-CMVLacZ) or hypoxia response elements controlling (AAV-H9LacZ) LacZ expression were packaged in AAV9 or AAV1 capsid and injected into mice through the jugular vein 1 hour after MCAO or 4 weeks after the induction of angiogenesis. LacZ gene expression was analyzed in the brain and other organs 5 days after LacZ vector injection. Results-: LacZ expression was detected in the peri-infarct region of AAV9-CMVLacZ and AAV9-H9LacZ-injected MCAO mice and the brain angiogenic foci of AAV9-CMVLacZ-injected mice. Minimum LacZ expression was detected in the brain of AAV1-CMVLacZ-injected mice. Robust LacZ expression was found in the liver and heart of AAV-CMVLacZ-injected mice, but not in AAV9-H9LacZ-injected mice. Conclusions-: ssAAV9 could be a useful tool to deliver therapeutic genes to the ischemic stroke lesion or brain angiogenic foci.