Weekly Cyclodextrin Administration Normalizes Cholesterol Metabolism in Nearly Every Organ of the Niemann-Pick Type C1 Mouse and Markedly Prolongs Life

Abstract

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 Ϫ/Ϫ mouse, s.c. with ␤-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 Ϫ/Ϫ 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. (Pediatr Res 68: 309-315, 2010)

Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann–Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease

“…The doses of 0-4000 mg/kg HPBCD used in this study were selected based on previous reports. [7][8][9] In addition, the upper dose (20000 mg/kg) of HPBCD does not have any adverse effects in acute toxicity in Npc1 −/− mice, as found in our previous study.…”

“…Previous reports have shown that subcutaneous administration of HPBCD (4000 mg/kg) every week is effective in Npc1 −/− mice. [7][8][9]17) In the current study, we found that subcutaneous injection every week of HPBCD could not maintain serum concentrations for a long time, but survival was clearly improved. However, there are no data on the effects of other frequencies of administration (e.g., every day, twice a week, or continuous infusion) of HPBCD.…”

“…Some previous reports have also demonstrated that just a single or weekly subcutaneous injection of HPBCD can significantly prolong life-span and improve pathophysiological changes in Npc1 −/− mice. [7][8][9]17) These findings suggest that transient increases in HPBCD, rather than maintaining blood levels, is required to exert effectiveness of HPBCD against NPC disease.…”

“…Some reports have shown that HPBCD improves cholesterol sequestration in organs and prolongs the lifespan in Npc1 null mice, suggesting that HPBCD is a promising drug candidate against NPC disease. [7][8][9][10] Recently, Matsuo et al 4) reported the effectiveness of HPBCD in treatment of two Japanese patients with NPC disease. One patient was started with intravenous infusion of 80 mg/kg HPBCD for 8 h twice a week, and another patient was started with 80 mg/kg HPBCD for 8 h three times a week.…”

Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin

“…HPβCD is thought to work primarily through cholesterol modulation (Ramirez et al 2010), but it has been shown to complex with other phospholipids and lipids within cells (Zidovetzki and Levitan 2007). Cyclodextrins have been studied in many cellular and organ systems and can affect cellular cholesterol content within hours (Taylor et al 2012), consistent with the timing of injury from ICV injection.…”