title: Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II.
abstract: Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantation (BMT) or enzyme replacement therapy, although BMT has been shown to be effective for other neurodegenerative MPSs, such as Hurler syndrome. In this study, we demonstrated that lentiviral isogeneic hematopoietic stem cell (HSC) gene therapy corrected neuronal manifestations by ameliorating lysosomal storage and autophagic dysfunction in the brains of MPS II mice. IDS-transduced HSCs increased enzyme activity both in various visceral organs and the CNS. Decreased levels of GAGs were observed in many organs, including cerebra, after transplantation of IDS-transduced HSCs. In addition, lentiviral HSC gene therapy normalized the secondary accumulation of autophagic substrates, such as p62 and ubiquitin-protein conjugates, in cerebra. Furthermore, in contrast to naive MPS II mice, there was no deterioration of neuronal function observed in transplant recipients. These results indicated that lentiviral HSC gene therapy is a promising approach for the treatment of CNS lesions in MPS II.
authors.affiliation: 1 Department of Pediatrics, Jikei University School of Medicine , Tokyo 105-8461, Japan .|2 Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine , Tokyo 105-8461, Japan .
authors.forename: Taichi
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: 2 Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine , Tokyo 105-8461, Japan .
authors.forename: Yohta
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: 3 Department of Pediatrics, Kitasato University School of Medicine , Kanagawa 252-0374, Japan .
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Akiyama
authors.affiliation: 2 Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine , Tokyo 105-8461, Japan .
authors.forename: Takashi
authors.initials: T
authors.lastname: Higuchi
authors.affiliation: 4 Division of Neuropathology, Department of Pathology, Jikei University School of Medicine , Tokyo 105-8461, Japan .
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: 1 Department of Pediatrics, Jikei University School of Medicine , Tokyo 105-8461, Japan .|2 Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine , Tokyo 105-8461, Japan .
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: 5 Advanced Clinical Research Center, Institute of Neurological Disorders , Kanagawa 215-0026, Japan .
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Eto
authors.affiliation: 1 Department of Pediatrics, Jikei University School of Medicine , Tokyo 105-8461, Japan .|2 Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine , Tokyo 105-8461, Japan .
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ida
authors.affiliation: 1 Department of Pediatrics, Jikei University School of Medicine , Tokyo 105-8461, Japan .|2 Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine , Tokyo 105-8461, Japan .
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007066:Iduronate Sulfatase / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016532:Mucopolysaccharidosis II / Q000235:genetics / Q000628:therapy*; D014161:Transduction, Genetic
chemical_list: D006023:Glycoproteins; D006025:Glycosaminoglycans; C018322:IDS protein, human; D007066:Iduronate Sulfatase