title: Reduced ischemic injury after stroke in mice by angiogenic gene delivery via ultrasound-targeted microbubble destruction.
abstract: Angiogenic gene therapy in patients with cerebral infarcts may have clinical benefit, but its potential is diminished by the difficulty of introducing genes into the brain. We evaluated the safety and efficacy of ultrasound-targeted microbubble destruction (UTMD) for delivery of genes to the brains of normal mice and after transient middle cerebral artery occlusion. In normal mice, disruption of the blood-brain barrier detected with trypan blue staining was reversible within 24 hours of a single UTMD administration. Expression of reporter genes in the brain after UTMD demonstrated successful targeted gene delivery and transfection. Decreased neurologic function after transient middle cerebral artery occlusion was attenuated versus controls at 7 days after UTMD delivery of vascular endothelial growth factor. Ultrasound-targeted microbubble destruction delivery of the VEGF gene resulted in decreased infarct areas, increased vessel density, and reduced apoptosis versus controls. There was no evidence of permanent brain injury throughout the study. Thus, UTMD was a safe, minimally invasive, effective technique for gene delivery to the brain. Vascular endothelial growth factor transfection of brain cells conferred beneficial effects on histopathologic parameters and neurologic function, and stimulated angiogenesis in a mouse stroke model.
authors.affiliation: From the Second Affiliated Hospital of Harbin Medical University, Harbin, China (H-BW, LY, LS, Jiang Wu, HT); and Toronto General Research Institute, University Health Network (H-BW, LY, Jun Wu, LS, RDW, R-KL); and Division of Cardiac Surgery, Department of Surgery, University of Toronto (H-BW, LY, Jun Wu, LS, RDW, R-KL), Toronto, Ontario, Canada.
authors.forename: Han-Bing
authors.initials: HB
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.forename: Hai
authors.initials: H
authors.lastname: Tian
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001808:Blood Vessels / Q000473:pathology; D001812:Blood-Brain Barrier / Q000473:pathology; D020520:Brain Infarction / Q000209:etiology* / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000473:pathology; D051379:Mice; D045423:Microbubbles / Q000627:therapeutic use*; D018919:Neovascularization, Physiologic; D009460:Neurologic Examination; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D014343:Trypan Blue; D014465:Ultrasonics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000627:therapeutic use*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D010751:Phosphopyruvate Hydratase; D014343:Trypan Blue