HPGCD Outperforms HPBCD as a Potential Treatment for Niemann‐Pick Disease Type C During Disease Modeling with iPS Cells

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. Stem Cells 2015;33:1075–1088

[1]  G. Daley,et al.  Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction. , 2013, Cell stem cell.

[2]  N. Fujii,et al.  Efficient and Reproducible Myogenic Differentiation from Human iPS Cells: Prospects for Modeling Miyoshi Myopathy In Vitro , 2013, PloS one.

[3]  Katsuhiro Yoshikawa,et al.  Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. , 2013, Cell stem cell.

[4]  D. Begley,et al.  Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood–brain barrier permeability , 2013, Journal of Inherited Metabolic Disease.

[5]  M. Hamasaki,et al.  Pathogenic Mutation of ALK2 Inhibits Induced Pluripotent Stem Cell Reprogramming and Maintenance: Mechanisms of Reprogramming and Strategy for Drug Identification , 2012, Stem cells.

[6]  Forbes D Porter,et al.  Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1. , 2012, Human molecular genetics.

[7]  F. Sedel,et al.  Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C , 2012, Orphanet Journal of Rare Diseases.

[8]  A. Ballabio,et al.  Autophagy in lysosomal storage disorders , 2012, Autophagy.

[9]  A. Bradley,et al.  Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells , 2011, Nature.

[10]  Naoki Nishishita,et al.  Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors , 2011, Proceedings of the National Academy of Sciences.

[11]  I. Sancho-Martinez,et al.  Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. , 2011, Cell stem cell.

[12]  K. Motoyama,et al.  Recent Findings on Safety Profiles of Cyclodextrins, Cyclodextrin Conjugates, and Polypseudorotaxanes , 2011 .

[13]  Fred H. Gage,et al.  A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells , 2010, Cell.

[14]  J. Repa,et al.  Weekly Cyclodextrin Administration Normalizes Cholesterol Metabolism in Nearly Every Organ of the Niemann-Pick Type C1 Mouse and Markedly Prolongs Life , 2010, Pediatric Research.

[15]  Shinsuke Yuasa,et al.  Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. , 2010, Cell stem cell.

[16]  Kristopher J. L. Irizarry,et al.  Abnormal gene expression in cerebellum of Npc1−/− mice during postnatal development , 2010, Brain Research.

[17]  F. Maxfield,et al.  Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells , 2010, Proceedings of the National Academy of Sciences.

[18]  M. Baumgartner,et al.  Recommendations on the diagnosis and management of Niemann-Pick disease type C. , 2009, Molecular genetics and metabolism.

[19]  M. Hasegawa,et al.  Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome , 2009, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[20]  D. Ory,et al.  Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression , 2009, PloS one.

[21]  A. Lieberman,et al.  Tau deletion exacerbates the phenotype of Niemann-Pick type C mice and implicates autophagy in pathogenesis. , 2009, Human molecular genetics.

[22]  J. Repa,et al.  Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse , 2009, Proceedings of the National Academy of Sciences.

[23]  James A. Thomson,et al.  Induced pluripotent stem cells from a spinal muscular atrophy patient , 2009, Nature.

[24]  Shulan Tian,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[25]  Masaaki Komatsu,et al.  Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient Mice , 2007, Cell.

[26]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[27]  M. Patterson,et al.  Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study , 2007, The Lancet Neurology.

[28]  A. Lieberman,et al.  Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. , 2007, Human molecular genetics.

[29]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[30]  Atul Mehta,et al.  Lysosomal Storage Disorders , 2005 .

[31]  Tsutomu Chiba,et al.  Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells , 2005, Nature Biotechnology.

[32]  Chikara Furusawa,et al.  Characterization of mesendoderm: a diverging point of the definitive endoderm and mesoderm in embryonic stem cell differentiation culture , 2005, Development.

[33]  M. Michikawa,et al.  Altered Cholesterol Metabolism in Niemann-Pick Type C1 Mouse Brains Affects Mitochondrial Function* , 2005, Journal of Biological Chemistry.

[34]  F. Camargo,et al.  Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease. , 2001, Life sciences.

[35]  H. Ninomiya,et al.  [Niemann-Pick disease type C]. , 2001, Nihon rinsho. Japanese journal of clinical medicine.

[36]  R. Wattiaux,et al.  Identification of HE1 as the second gene of Niemann-Pick C disease. , 2000, Science.

[37]  Takeshi Noda,et al.  LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing , 2000, The EMBO journal.

[38]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[39]  F. Hirayama,et al.  Cyclodextrin Drug Carrier Systems. , 1998, Chemical reviews.

[40]  W. Pavan,et al.  Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. , 1997, Science.

[41]  K. G. Coleman,et al.  Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. , 1997, Science.

[42]  K. Uekama,et al.  Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. , 1997, Journal of pharmaceutical sciences.

[43]  G. Kroemer,et al.  Chloromethyl-X-Rosamine is an aldehyde-fixable potential-sensitive fluorochrome for the detection of early apoptosis. , 1996, Cytometry.

[44]  R. Dwek,et al.  N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. , 1994, The Journal of biological chemistry.

[45]  G. Steele,et al.  Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D. Frank,et al.  Cyclodextrin nephrosis in the rat. , 1976, The American journal of pathology.

[47]  R. Lovell-Badge,et al.  Multipotent cell lineages in early mouse development depend on SOX2 function. , 2003, Genes & development.