title: Neonatal gene therapy of MPS I mice by intravenous injection of a lentiviral vector.
abstract: Mucopolysaccharidosis type I (MPS I) is a lysosomal glycosaminoglycan (GAG) storage disorder caused by deficiency of alpha-l-iduronidase (IDUA). In this study, we evaluated the potential to perform gene therapy for MPS I by direct in vivo injection of a lentiviral vector, using an IDUA gene knockout murine model. We compared the efficacy in newborn versus young adult MPS I mice of a single intravenous injection of the lentiviral vector. The extent of transduction was dose-dependent, with the liver receiving the highest level of vector, but other somatic organs reaching almost the same level. The phenotypic manifestations of disease were partially improved in the mice treated as young adults, but were nearly normalized at every end-point measured in the mice treated as neonates. In the neonatally treated mice, the expressed IDUA activity resulted in decreased GAG storage, prevention of skeletal abnormalities, a more normal gross appearance, and improved survival. Most strikingly, significant levels of IDUA enzyme were produced in the brain of mice treated as neonates, with transduction of neurons at high levels. The sustained expression of enzymatically active IDUA in multiple organs had a significant beneficial effect on the phenotypic abnormalities of MPS I, which may be translated to clinical gene therapy of patients with Hurler disease.
authors.affiliation: Department of Pediatrics, Division of Research Immunology/Bone Marrow Transplantation, The Saban Research Institute at Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Denise
authors.initials: D
authors.lastname: Carbonaro
authors.forename: Karen
authors.initials: K
authors.lastname: Pepper
authors.forename: Denise
authors.initials: D
authors.lastname: Petersen
authors.forename: Shundi
authors.initials: S
authors.lastname: Ge
authors.forename: Holly
authors.initials: H
authors.lastname: Jackson
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Rex
authors.initials: R
authors.lastname: Moats
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000002:abnormalities / Q000378:metabolism; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007275:Injections, Intravenous; D016086:Lentivirus / Q000235:genetics*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D009474:Neurons / Q000378:metabolism; D013455:Sulfur / Q000737:chemistry; D015996:Survival Rate
chemical_list: D018076:DNA, Complementary; D006025:Glycosaminoglycans; D013455:Sulfur; D007068:Iduronidase