Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease

Niemann-Pick type C (NPC) is a neurodegenerative disorder characterized by greatly altered somatic cholesterol metabolism. The NPC1 gene has recently been cloned and shown to have sequence homology to other sterol-sensing pro teins. We have used a mouse model with a disrupted npc1 gene to study the e ffects of the cholesterol-mobilizing compound, 2-hydroxypropyl-beta -cyclod extrins (HPBCD), on the clinical course of this disorder. Treatment with tw o HPBCDs, with varying levels of 2-hydroxypropyl substitution, had effects in delaying neurological symptoms and in decreasing liver cholesterol stora ge while a third HPBCD was without effect. The ameliorating effect was not improved by longer exposure times (commencement of exposure in utero), howe ver, it is not known if there is transplacental transfer of HPBCDs. The com bination of HPBCD with probucol or nifedipine (which have previously been s hown to lower liver cholesterol in this animal model) markedly decreased li ver storage of unesterified cholesterol without altering the depressed leve ls of esterified cholesterol. The slight effects of the HPBCDs on neurologi cal symptoms may be partially due to their apparent non-permeation of the b lood-brain barrier (BBB). This non-permeation was assayed with radioactive tracers and was also present in the mdr1a knockout mice which have greatly increased BBB permeability for many drugs. Intrathecal delivery of HPBCD by an Alzet(R) osmotic minipump did not improve its efficacy in ameliorating neurological symptoms. (C) 2001 Elsevier Science Inc. All rights reserved.