Kert Mätlik1, Usama Abo-Ramadan1, Brandon K Harvey2, Urmas Arumäe3, Mikko Airavaara4. 1. Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland. 2. Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA. 3. Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland; Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia. 4. Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland. Electronic address: mikko.airavaara@helsinki.fi.
Abstract
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 peri-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 peri-infarct region of cortical ischemic lesion in rats 2days 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 peri-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 over-expression of genes to the peri-infarct region in a rat stroke model. This method will be useful for studying the action of specific proteins in peri-infarct region during the recovery process.
BACKGROUND: For strokepatients the recovery of cognitive and behavioral functions is often incomplete. Functional recovery is thought to be mediated largely by connectivity rearrangements in the peri-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 peri-infarct region of cortical ischemic lesion in rats 2days 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 peri-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 over-expression of genes to the peri-infarct region in a ratstroke model. This method will be useful for studying the action of specific proteins in peri-infarct region during the recovery process.
Authors: Mikko Airavaara; Brandon K Harvey; Merja H Voutilainen; Hui Shen; Jenny Chou; Päivi Lindholm; Maria Lindahl; Raimo K Tuominen; Mart Saarma; Barry Hoffer; Yun Wang Journal: Cell Transplant Date: 2011-09-22 Impact factor: 4.064
Authors: Mikko Airavaara; Matt J Chiocco; Doug B Howard; Katie L Zuchowski; Johan Peränen; Chao Liu; Shengyun Fang; Barry J Hoffer; Yun Wang; Brandon K Harvey Journal: Exp Neurol Date: 2010-06-02 Impact factor: 5.330
Authors: Li Zhang; Michael Chopp; Rui Lan Zhang; Lei Wang; Jing Zhang; Ying Wang; Yier Toh; Manoranjan Santra; Mei Lu; Zheng Gang Zhang Journal: PLoS One Date: 2010-06-11 Impact factor: 3.240
Authors: Brandon K Harvey; Mikko Airavaara; Jason Hinzman; Emily M Wires; Matthew J Chiocco; Douglas B Howard; Hui Shen; Greg Gerhardt; Barry J Hoffer; Yun Wang Journal: PLoS One Date: 2011-08-10 Impact factor: 3.240
Authors: Kuan-Yin Tseng; Jenni E Anttila; Konstantin Khodosevich; Raimo K Tuominen; Maria Lindahl; Andrii Domanskyi; Mikko Airavaara Journal: Mol Ther Date: 2017-09-21 Impact factor: 11.454