Intravenous Delivery of Adeno-Associated Viral Vector Serotype 9 Mediates Effective Gene Expression in Ischemic Stroke Lesion and Brain Angiogenic Foci
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.
- adeno-associated viral vector serotype 9
- intravenous delivery
- peri-infarct region
- Received April 30, 2012.
- Accepted September 14, 2012.
- © 2012 American Heart Association, Inc.