title: Normalization of Hepatic Homeostasis in theNpc1nmf164Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat.
abstract: Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued thesein vitroobservations in two murine models of NP-C disease.Npc1nmf164mice, which express a missense mutation in theNpc1gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 μm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null (Npc1-/-) and missense (Npc1nmf164) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of theNpc1locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease.
authors.affiliation: From the School of Biological Sciences and andrew.munkacsi@vuw.ac.nz.|Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New Zealand.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Munkacsi
authors.affiliation: From the School of Biological Sciences and.
authors.forename: Natalie
authors.initials: N
authors.lastname: Hammond
authors.affiliation: From the School of Biological Sciences and.
authors.forename: Remy T
authors.initials: RT
authors.lastname: Schneider
authors.affiliation: From the School of Biological Sciences and.
authors.forename: Dinindu S
authors.initials: DS
authors.lastname: Senanayake
authors.affiliation: the Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago 683-8503, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Callaghan Innovation, Lower Hutt 5040, New Zealand.
authors.forename: Kirill
authors.initials: K
authors.lastname: Lagutin
authors.affiliation: Callaghan Innovation, Lower Hutt 5040, New Zealand.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Bloor
authors.affiliation: the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: the Department of Physiology and Neurobiology and the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Maue
authors.affiliation: the Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Fannie W
authors.initials: FW
authors.lastname: Chen
authors.affiliation: the Department of Medicine and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hernandez-Ono
authors.affiliation: the Departments of Physiology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Dahlson
authors.affiliation: the Departments of Physiology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Repa
authors.affiliation: the Department of Medicine and.
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
authors.affiliation: the Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Yiannis A
authors.initials: YA
authors.lastname: Ioannou
authors.affiliation: the Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032 sls37@columbia.edu.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Sturley
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D001055:Apolipoproteins B; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D000077337:Vorinostat; D002784:Cholesterol
keywords: Saccharomyces cerevisiae; cholesterol; cholesterol regulation; histone deacetylase inhibitor (HDAC inhibitor) (HDI); lipid trafficking; lysosomal storage disease; neurodegenerative disease; sphingolipid; yeast