title: Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.
abstract: Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: bgurda@vet.upenn.edu.
authors.forename: Brittney L
authors.initials: BL
authors.lastname: Gurda
authors.affiliation: University of Nantes Medical School, Nantes, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: De Guilhem De Lataillade
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: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhu
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 Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bagel
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 Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Tracey
authors.initials: T
authors.lastname: Sikora
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: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.affiliation: Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Yox
authors.affiliation: Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Steet
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Therese
authors.initials: T
authors.lastname: Ruane
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
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
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Margret
authors.initials: M
authors.lastname: Casal
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Ponder
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002493:Central Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D005966:Glucuronidase / Q000134:cerebrospinal fluid / Q000235:genetics*; D006025:Glycosaminoglycans / Q000378:metabolism; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008297:Male; D016538:Mucopolysaccharidosis VII / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000628:therapy*
chemical_list: D006025:Glycosaminoglycans; D005966:Glucuronidase