title: Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease.
abstract: Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. We show that subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-β-cyclodextrin (HPβCD) to cats with NPC disease ameliorated hepatic disease, but doses sufficient to reduce neurological disease resulted in pulmonary toxicity. However, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near-normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. These studies in a feline animal model have provided critical data on efficacy and safety of drug administration directly into the central nervous system that will be important for advancing HPβCD into clinical trials.
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. vite@vet.upenn.edu.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Vite
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Bagel
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Swain
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Prociuk
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Tracey U
authors.initials: TU
authors.lastname: Sikora
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Veronika M
authors.initials: VM
authors.lastname: Stein
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Therese
authors.initials: T
authors.lastname: Ruane
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ward
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Crooks
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mauldin
authors.affiliation: Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, NJ 08560, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Stellar
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson and Johnson, Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: De Meulder
authors.affiliation: Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, NJ 08560, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kao
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Cristin
authors.initials: C
authors.lastname: Davidson
authors.affiliation: INSERM U820; EA4611, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000375:Aging / Q000473:pathology; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001259:Ataxia / Q000097:blood / Q000150:complications / Q000473:pathology; D001309:Auditory Threshold; D064026:Calbindins / Q000378:metabolism; D002415:Cats; D016923:Cell Death; D002946:Cisterna Magna / Q000473:pathology* / Q000503:physiopathology*; D005455:Fluorescent Antibody Technique; D005678:G(M2) Ganglioside / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007279:Injections, Subcutaneous; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000150:complications / Q000473:pathology; D008168:Lung / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*; D013194:Staining and Labeling; D016019:Survival Analysis; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D064026:Calbindins; D047392:beta-Cyclodextrins; D005678:G(M2) Ganglioside; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000410:Alanine Transaminase