title: Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model.
abstract: Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model.
authors.affiliation: Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA. Department of Biological Sciences, University of Notre Dame, 103 Galvin Life Sciences, Notre Dame, IN 46556, USA.
authors.forename: Md Suhail
authors.initials: MS
authors.lastname: Alam
authors.affiliation: Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA. Department of Biological Sciences, University of Notre Dame, 103 Galvin Life Sciences, Notre Dame, IN 46556, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Getz
authors.affiliation: Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA. Department of Biological Sciences, University of Notre Dame, 103 Galvin Life Sciences, Notre Dame, IN 46556, USA. khaldar@nd.edu.
authors.forename: Kasturi
authors.initials: K
authors.lastname: Haldar
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D016019:Survival Analysis; D000077337:Vorinostat; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011092:Polyethylene Glycols; D000077337:Vorinostat