title: Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption.
abstract: The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption that we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration.
authors.affiliation: Department of Radiology, Weill Cornell Medical College, 516 E 72nd Street, New York, NY 10021, USA.
authors.forename: Conor P
authors.initials: CP
authors.lastname: Foley
authors.affiliation: Department of Neurosurgery, Weill Cornell Medical College, 525 East 68 Street, New York, NY 10065, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Rubin
authors.affiliation: Department of Neurosurgery, Weill Cornell Medical College, 525 East 68 Street, New York, NY 10065, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Santillan
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA.
authors.forename: Dolan
authors.initials: D
authors.lastname: Sondhi
authors.affiliation: Department of Radiology, Weill Cornell Medical College, 516 E 72nd Street, New York, NY 10021, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Dyke
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.affiliation: Department of Neurosurgery, Weill Cornell Medical College, 525 East 68 Street, New York, NY 10065, USA.
authors.forename: Y Pierre
authors.initials: YP
authors.lastname: Gobin
authors.affiliation: Department of Radiology, Weill Cornell Medical College, 516 E 72nd Street, New York, NY 10021, USA.|Department of Genetic Medicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Ballon
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000033:anatomy & histology / Q000187:drug effects*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000821:virology*; D057785:Catheters; D000229:Dependovirus; D004232:Diuretics / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007269:Injections, Intra-Arterial; D008279:Magnetic Resonance Imaging; D008297:Male; D008353:Mannitol / Q000494:pharmacology*; D051379:Mice; D009995:Osmosis; D014018:Tissue Distribution; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D004232:Diuretics; C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D008353:Mannitol
keywords: Adeno-associated virus; Blood brain barrier; Intra-arterial; MRI; Neural drug delivery