title: Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna.
abstract: Adeno-associated virus serotype 9 (AAV9) vectors have recently been shown to transduce cells throughout the central nervous system of nonhuman primates when injected into the cerebrospinal fluid (CSF), a finding which could lead to a minimally invasive approach to treat genetic and acquired diseases affecting the entire CNS. We characterized the transduction efficiency of two routes of vector administration into the CSF of cynomolgus macaques-lumbar puncture, which is typically used in clinical practice, and suboccipital puncture, which is more commonly used in veterinary medicine. We found that delivery of vector into the cisterna magna via suboccipital puncture is up to 100-fold more efficient for achieving gene transfer to the brain. In addition, we evaluated the inflammatory response to AAV9-mediated GFP expression in the nonhuman primate CNS. We found that while CSF lymphocyte counts increased following gene transfer, there were no clinical or histological signs of immune toxicity. Together these data indicate that delivery of AAV9 into the cisterna magna is an effective method for achieving gene transfer in the CNS, and suggest that adapting this uncommon injection method for human trials could vastly increase the efficiency of gene delivery.
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Hinderer
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Vite
authors.affiliation: Department of Basic Medical Sciences, Section of Anatomy, University of the West Indies , Kingston, Jamaica.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Louboutin
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Grant
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Bote
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Radiology, Hospital of the University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Pukenas
authors.affiliation: Department of Radiology, Hospital of the University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hurst
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson