Attenuating sterol synthesis in WT and NPC mice brains

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DESCRIPTION (provided by applicant): Our long-term goal is to provide new and mechanistic links between cholesterol metabolism and neuropathology in the brain. In this application, we use the Niemann-Pick type C1 mouse as our model system. Niemann-Pick type C (NPC) disease is a fatal autosomal recessive neurovisceral disorder characterized by clinically progressive hepatosplenomegaly and neurodegeneration in the central nervous system (CNS). It is characterized by the cellular accumulation of unesterified cholesterol, sphingomyelin, glycolipids, and other lipids within the endosomal/lysosomal system. Currently, there is no cure for this disease. Whether cholesterol accumulation and/or glycosphingolipid accumulation in the brain serves as a primary causative agent for this disease is not known, and has been under debate. We have recently demonstrated neuronal cholesterol accumulation in the brains of very young NPC1 mice. We now propose to treat normal and NPC1 mice with a specific cholesterol synthesis inhibitor (squalene synthase inhibitor; SSI) CP-340868 (developed by Pfizer, Inc.) to evaluate the relationship between cholesterol accumulation and ganglioside accumulation in the NPC1 mice brains. We will also test the feasibility of using SSI as a potential drug therapy to treat the NPC1 disease. Our 3 specific aims are: Specific Aim 1: a. To compare the dose effect of SSI CP-340858 and the HMG-CoA reductase inhibitor Iovastatin in blocking cholesterol synthesis, in the brains and the livers of mice. b. To examine the short-term effect of SSI CP-340868 on the accumulations of cholesterol, glycolipids, and various inflammatory cells in normal and NPC1 mice brains. Specific Aim 2: To examine the intermediate-term effect of SSI CP-340858 at 2 different doses on neurodegeneration, Purkinje cell loss, weight loss, and lack of motor control, and to examine the lipid accumulation and inflammatory cell accumulation in various regions of the brains in normal and NPC1 mice. Specific Aim 3: To examine the long-term effect of SSI CP-340868 at 2 different doses on life spans of normal and NPC1 mice.