1. Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease.
- Author
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Vite CH, Bagel JH, Swain GP, Prociuk M, Sikora TU, Stein VM, O'Donnell P, Ruane T, Ward S, Crooks A, Li S, Mauldin E, Stellar S, De Meulder M, Kao ML, Ory DS, Davidson C, Vanier MT, and Walkley SU
- Subjects
- 2-Hydroxypropyl-beta-cyclodextrin, Aging pathology, Alanine Transaminase blood, Animals, Ataxia blood, Ataxia complications, Ataxia pathology, Auditory Threshold, Calbindins metabolism, Cats, Cell Death, Fluorescent Antibody Technique, G(M2) Ganglioside metabolism, Inflammation complications, Inflammation pathology, Injections, Subcutaneous, Liver pathology, Liver Diseases blood, Liver Diseases complications, Liver Diseases pathology, Lung pathology, Niemann-Pick Disease, Type C blood, Niemann-Pick Disease, Type C complications, Purkinje Cells metabolism, Staining and Labeling, Survival Analysis, beta-Cyclodextrins administration & dosage, Cisterna Magna pathology, Cisterna Magna physiopathology, Niemann-Pick Disease, Type C drug therapy, Niemann-Pick Disease, Type C physiopathology, Purkinje Cells pathology, beta-Cyclodextrins therapeutic use
- 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., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
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