AAV-mediated targeting of gene expression to the peri-infarct region in rat cortical stroke model

Background: For stroke patients the recovery of cognitive and behavioral functions is often incomplete. Functional recovery is thought to be mediated largely by connectivity rearrangements in the pen-infarct region. A method for manipulating gene expression in this region would be useful for identifying new recovery-enhancing treatments. New method: We have characterized a way of targeting adeno-associated virus (AAV) vectors to the pen-infarct region of cortical ischemic lesion in rats 2 days after middle cerebral artery occlusion (MCAo). Results: We used magnetic resonance imaging (MRI) to show that the altered properties of post-ischemic brain tissue facilitate the spreading of intrastriatally injected nanoparticles toward the infarct. We show that subcortical injection of green fluorescent protein-encoding dsAAV7-GFP resulted in transduction of cells in and around the white matter tract underlying the lesion, and in the cortex proximal to the lesion. A similar result was achieved with dsAAV7 vector encoding the cerebral dopamine neurotrophic factor (CDNF), a protein with therapeutic potential. Comparison with existing methods: Viral vector-mediated intracerebral gene delivery has been used before in rodent models of ischemic injury. However, the method of targeting gene expression to the pen-infarct region, after the initial phase of ischemic cell death, has not been described before. Conclusions: We demonstrate a straightforward and robust way to target AAV vector-mediated overexpression of genes to the pen-infarct region in a rat stroke model. This method will be useful for studying the action of specific proteins in pen-infarct region during the recovery process. (C) 2014 Elsevier B.V. All rights reserved.