title: HPGCD outperforms HPBCD as a potential treatment for Niemann-Pick disease type C during disease modeling with iPS cells.
abstract: Niemann-Pick disease type C (NPC) is a lysosomal storage disease characterized by abnormal accumulation of free cholesterol and glycolipids. Here, we established induced pluripotent stem cell (iPSC) lines from NPC patients. Hepatocyte-like cells (HLCs) and neural progenitors derived from the iPSC lines accumulated cholesterol and displayed impaired autophagy and ATP production. A molecular signature related to lipid metabolism was also impaired in the NPC-iPSC-derived HLCs. These findings indicate that iPSC-derived cells can phenocopy human NPC. We also newly found that 2-hydroxypropyl-γ-cyclodextrin (HPGCD) could reduce the cholesterol accumulation and restore the functional and molecular abnormalities in the NPC patient-derived cells, and do so more effectively than 2-hydroxypropyl-β-cyclodextrin treatment. In addition, NPC model mice showed an improved liver status and prolonged survival with HPGCDs. Thus, iPSC lines derived from patient cells are powerful tools to study cellular models of NPC, and HPGCD is a potential new drug candidate for future treatment of this disease.
authors.affiliation: Department of Cell Modulation, Institute of Molecular Embryology and Genetics.
authors.forename: Minami
authors.initials: M
authors.lastname: Soga
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishitsuka
authors.forename: Makoto
authors.initials: M
authors.lastname: Hamasaki
authors.forename: Kaori
authors.initials: K
authors.lastname: Yoneda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Furuya
authors.forename: Muneaki
authors.initials: M
authors.lastname: Matsuo
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
authors.forename: Noemi
authors.initials: N
authors.lastname: Fusaki
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.forename: Fumio
authors.initials: F
authors.lastname: Endo
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
authors.forename: Takumi
authors.initials: T
authors.lastname: Era
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D018920:Coculture Techniques; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome; D047392:beta-Cyclodextrins / Q000494:pharmacology* / Q000627:therapeutic use; D047408:gamma-Cyclodextrins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; C479659:hydroxypropyl-gamma-cyclodextrin; D000073738:2-Hydroxypropyl-beta-cyclodextrin
keywords: Experimental models; Induced pluripotent stem cells; Niemann-Pick disease type C; Transgene-free