title: A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I.
abstract: Mucopolysaccharidosis type I (MPS I) is an inherited α-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-lived, providing a very narrow window to assess the long-term efficacy of therapeutic interventions. They also develop thymic lymphomas, making the assessment of potential tumorigenicity of human stem cell transplantation problematic. We therefore developed a new MPS I model based on a NOD/SCID/Il2rγ (NSG) background. This model lives longer than 1 year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells were found to readily engraft, with human cells detectable for at least 1 year posttransplantation. This new MPS I model is thus suitable for preclinical testing of novel pluripotent stem cell-based therapy approaches.
authors.affiliation: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Mendez
authors.affiliation: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Stover
authors.affiliation: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Rangel
authors.affiliation: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brick
authors.affiliation: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Nethercott
authors.affiliation: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Torres
authors.affiliation: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Khalid
authors.affiliation: King's College, London, Institute of Psychiatry, Psychology & Neuroscience , London, UK.
authors.forename: Andrew Ms
authors.initials: AM
authors.lastname: Wong
authors.affiliation: King's College, London, Institute of Psychiatry, Psychology & Neuroscience , London, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.affiliation: Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine , Irvine, California, USA ; Department of Biomedical Engineering, Gavin Herbert Eye Institute, University of California, Irvine , Irvine, California, USA.
authors.forename: James V
authors.initials: JV
authors.lastname: Jester
authors.affiliation: Department of Pathology and Laboratory Medicine, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine , Irvine, California, USA ; Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine , Irvine, California, USA.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Monuki
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center , Torrance, California, USA.
authors.forename: Cian
authors.initials: C
authors.lastname: McGuire
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center , Torrance, California, USA.
authors.forename: Steven Q
authors.initials: SQ
authors.lastname: Le
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center , Torrance, California, USA.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Kan
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center , Torrance, California, USA.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Dickson
authors.affiliation: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Schwartz