title: Neonatal tolerance induction enables accurate evaluation of gene therapy for MPS I in a canine model.
abstract: High fidelity animal models of human disease are essential for preclinical evaluation of novel gene and protein therapeutics. However, these studies can be complicated by exaggerated immune responses against the human transgene. Here we demonstrate that dogs with a genetic deficiency of the enzyme α-l-iduronidase (IDUA), a model of the lysosomal storage disease mucopolysaccharidosis type I (MPS I), can be rendered immunologically tolerant to human IDUA through neonatal exposure to the enzyme. Using MPS I dogs tolerized to human IDUA as neonates, we evaluated intrathecal delivery of an adeno-associated virus serotype 9 vector expressing human IDUA as a therapy for the central nervous system manifestations of MPS I. These studies established the efficacy of the human vector in the canine model, and allowed for estimation of the minimum effective dose, providing key information for the design of first-in-human trials. This approach can facilitate evaluation of human therapeutics in relevant animal models, and may also have clinical applications for the prevention of immune responses to gene and protein replacement therapies.
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Hinderer
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
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 Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Katz
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Lin
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Choa
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bagel
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Fitzgerald
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Therese
authors.initials: T
authors.lastname: Langan
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Margret L
authors.initials: ML
authors.lastname: Casal
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: wilsonjm@mail.med.upenn.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D056947:Enzyme Replacement Therapy; D015316:Genetic Therapy; D005822:Genetic Vectors; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008059:Mucopolysaccharidosis I / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D019076:Transgenes
chemical_list: D006025:Glycosaminoglycans; D007068:Iduronidase
keywords: AAV; Gene therapy; Intrathecal; MPS I; Neonatal tolerance