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Systemic administration of 2‐hydroxypropyl‐β‐cyclodextrin to symptomatic Npc1‐deficient mice slows cholesterol sequestration in the major organs and improves liver function
Author(s) -
Lopez Adam M,
Terpack Sandi J,
Posey Kenneth S,
Liu Benny,
Ramirez Charina M,
Turley Stephen D
Publication year - 2014
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12285
Subject(s) - npc1 , cholesterol , medicine , niemann–pick disease , endocrinology , spleen , niemann–pick disease, type c , pharmacology , receptor , endosome
Summary In Niemann–Pick type C ( NPC ) disease, loss‐of‐function mutations in either NPC 1 or NPC 2 result in progressive accumulation of unesterified cholesterol ( UC ) and glycosphingolipids in all organs, leading to neurodegeneration, pulmonary dysfunction and sometimes liver failure. There is no cure for this disorder. Studies using primarily NPC mouse models have shown that systemic administration of 2‐hydroxypropyl‐β‐cyclodextrin (2 HP β CD ), starting in early neonatal life, diminishes UC accumulation in most organs, slows disease progression and extends lifespan. The key question now is whether delaying the start of 2 HP β CD treatment until early adulthood, when the amount of entrapped UC throughout the body is markedly elevated, has any of the benefits found when treatment begins at 7 days of age. In the present study, Npc1 −/− and Npc1 +/+ mice were given saline or 2 HP β CD subcutaneously at 49, 56, 63 and 70 days of age, with measurements of organ weights, liver function tests and tissue cholesterol levels performed at 77 days. In Npc1 −/− mice, treatment with 2 HP β CD from 49 days reduced whole‐liver cholesterol content at 77 days from 33.0 ± 1.0 to 9.1 ± 0.5 mg/organ. Comparable improvements were seen in other organs, such as the spleen, and in the animal as a whole. There was a transient increase in biliary cholesterol concentration in Npc1 −/− mice after 2 HP β CD . Plasma alanine aminotransferase and aspartate aminotransferase activities in 77‐day‐old 2 HP β CD ‐treated Npc1 −/− mice were reduced compared with saline‐treated controls. The lifespan of Npc1 −/− mice given 2 HP β CD marginally exceeded that of the saline‐treated controls (99 ± 1.1 vs 94 ± 1.4 days, respectively; P < 0.05). Thus, 2 HP β CD is effective in mobilizing entrapped cholesterol in late‐stage NPC disease leading to improved liver function.