betadex and Nerve-Degeneration

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.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Blood-Brain Barrier; Disease Models, Animal; Disease Progression; Fibroblasts; Histone Deacetylase Inhibitors; Hydroxamic Acids; Inflammation; Liver; Mice; Mutation; Nerve Degeneration; Niemann-Pick Disease, Type C; Polyethylene Glycols; Purkinje Cells; RNA, Messenger; Spleen; Survival Analysis; Vorinostat

Niemann-Pick type C1 (NPC1) disease arises from a mutation inactivating NPC1 protein that normally moves unesterified cholesterol from the late endosomal/lysosomal complex of cells to the cytosolic compartment for processing. As a result, cholesterol accumulates in every tissue of the body causing liver, lung, and CNS disease. Treatment of the murine model of this disease, the npc1 mouse, s.c. with β-cyclodextrin (4000 mg/kg) one time each week normalized cellular cholesterol metabolism in the liver and most other organs. At the same time, the hepatic dysfunction seen in the untreated npc1 mouse was prevented. The severity of cerebellar neurodegeneration also was ameliorated, although not entirely prevented, and the median lifespan of the animals was doubled. However, in contrast to these other organs, lung showed progressive macrophage infiltration with development of lipoid pneumonitis. These studies demonstrated that weekly cyclodextrin administration overcomes the lysosomal transport defect associated with the NPC1 mutation, nearly normalizes hepatic and whole animal cholesterol pools, and prevents the development of liver disease. Furthermore, this treatment slows cerebellar neurodegeneration but has little or no effect on the development of progressive pulmonary disease.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Anticholesteremic Agents; beta-Cyclodextrins; Biological Transport; Brain; Cholesterol; Disease Models, Animal; Drug Administration Schedule; Injections, Subcutaneous; Intracellular Signaling Peptides and Proteins; Liver; Liver Diseases; Lung; Lung Diseases; Macrophages; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Mutation; Nerve Degeneration; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Proteins; Time Factors

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; beta-Cyclodextrins; Calcium; Calpain; Cell Death; Cell Membrane; Cholesterol; Hippocampus; Humans; Nerve Degeneration; Neurons; Signal Transduction; tau Proteins