title: Convection-enhanced delivery of AAV2 in white matter--a novel method for gene delivery to cerebral cortex.
abstract: BACKGROUND
  Convection-enhanced delivery (CED) is currently under investigation for delivering therapeutic agents to subcortical targets in the brain. Direct delivery of therapies to the cerebral cortex, however, remains a significant challenge.
  
  
  METHODS
  We describe a novel method of targeting adeno-associated viral vector (AAV) mediated gene therapies to specific cerebral cortical regions by performing high volume, high flow rate infusions into underlying white matter in a large animal (porcine) model.
  
  
  RESULTS
  Infusion volumes of up to 700 μl at flow rates as high as 10 μl/min were successfully performed in white matter without adverse neurological sequelae. Co-infusion of AAV2/5-GFP with 0.2% Gadolinium in artificial CSF confirmed transgene expression in the deep layers of cerebral cortex overlying the infused areas of white matter.
  
  
  METHODS
  AAV-mediated gene therapies have been previously targeted to the cerebral cortex by performing intrathalamic CED and exploiting axonal transport. The novel method described in this study facilitates delivery of gene therapies to specific regions of the cerebral cortex without targeting deep brain structures.
  
  
  CONCLUSIONS
  AAV-mediated gene therapies can be targeted to specific cortical regions by performing CED into underlying white matter. This technique could be applied to the treatment of neurological disorders characterised by cerebral cortical degeneration.
authors.affiliation: Functional Neurosurgery Research Group, AMBI Laboratories, University of Bristol, BS10 5NB, UK.
authors.forename: N U
authors.initials: NU
authors.lastname: Barua
authors.forename: M
authors.initials: M
authors.lastname: Woolley
authors.forename: A S
authors.initials: AS
authors.lastname: Bienemann
authors.forename: D
authors.initials: D
authors.lastname: Johnson
authors.forename: M J
authors.initials: MJ
authors.lastname: Wyatt
authors.forename: C
authors.initials: C
authors.lastname: Irving
authors.forename: O
authors.initials: O
authors.lastname: Lewis
authors.forename: E
authors.initials: E
authors.lastname: Castrique
authors.forename: S S
authors.initials: SS
authors.lastname: Gill
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000821:virology*; D018481:Convection; D000229:Dependovirus; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007150:Immunohistochemistry; D057967:Infusions, Intraventricular; D008279:Magnetic Resonance Imaging; D009413:Nerve Fibers, Myelinated / Q000821:virology*; D013552:Swine; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins
keywords: Cerebral cortex; Convection-enhanced delivery; Gene therapy; White matter