title: Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I.
abstract: Enzyme replacement therapy has revolutionized the treatment of the somatic manifestations of lysosomal storage diseases (LSD), although it has been ineffective in treating central nervous system (CNS) manifestations of these disorders. The development of neurotrophic vectors based on novel serotypes of adeno-associated viruses (AAV) such as AAV9 provides a potential platform for stable and efficient delivery of enzymes to the CNS. We evaluated the safety and efficacy of intrathecal delivery of AAV9 expressing α-l-iduronidase (IDUA) in a previously described feline model of mucopolysaccharidosis I (MPS I). A neurological phenotype has not been defined in these animals, so our analysis focused on the biochemical and histological CNS abnormalities characteristic of MPS I. Five MPS I cats were dosed with AAV9 vector at 4-7 months of age and followed for 6 months. Treated animals demonstrated virtually complete correction of biochemical and histological manifestations of the disease throughout the CNS. There was a range of antibody responses against IDUA in this cohort which reduced detectable enzyme without substantially reducing efficacy; there was no evidence of toxicity. This first demonstration of the efficacy of intrathecal gene therapy in a large animal model of a LSD should pave the way for translation into the clinic.
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Hinderer
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Current address: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Brittney L
authors.initials: BL
authors.lastname: Gurda
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Section of Anatomy, Department of Basic Medical Sciences, 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, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pathobiology and 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 Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Department of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Tracey
authors.initials: T
authors.lastname: Sikora
authors.affiliation: Department of Pathobiology and 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 Pathobiology and 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 Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: wilsonjm@mail.med.upenn.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D002415:Cats; D002490:Central Nervous System / Q000473:pathology*; D000229:Dependovirus / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D007068:Iduronidase / Q000097:blood* / Q000134:cerebrospinal fluid*; D007278:Injections, Spinal; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009928:Organ Specificity
chemical_list: D007068:Iduronidase