Identification of a pharmaceutical compound that partially corrects the Niemann-Pick C phenotype in cultured cells

Niemann-Pick C (NPC) is an autosomal recessive lysosomal lipid storage disease characterized by progressive central nervous system degeneration. In cultured human NPC fibroblasts, LDL-derived cholesterol accumulates in ly- sosomes and endosomes, LDL-cholesterol transport from endocytic compartments to other cellular compartments is delayed, and LDL does not elicit normal homeostatic re- sponses. Currently, there is no therapy that delays the onset of neurological symptoms or prolongs the life span of NPC children. We have developed and implemented an ampho- tericin B-mediated cytotoxicity assay to screen for potential therapeutic drugs that induce cholesterol movement in cul- tured NPC cells. NPC cells are relatively resistant to ampho- tericin B killing due to intracellular sequestration of cellular cholesterol. The screen was carried out using simian virus 40-transformed ovarian granulosa cells from the npc nih mouse model of NPC disease. A library of 44,240 com- pounds was screened and 55 compounds were identified that promote amphotericin B-mediated killing of NPC cells. One compound, NP-27, corrected the NPC pheno- type by four different measures of cholesterol homeostasis. In addition to making NPC cells more sensitive to ampho- tericin B, NP-27 stimulated two separate cholesterol trans- port pathways and restored LDL stimulation of cholesterol esterification to near normal levels. —Liscum, L., E. Arnio, M. Anthony, A. Howley, S. L. Sturley, and M. Agler. Identifi- cation of a pharmaceutical compound that partially corrects the Niemann-Pick C phenotype in cultured cells. J. Lipid Res. 2002. 43: 1708-1717.