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Abstract
Niemann-Pick disease type C (NPC) is an autosomal recessive genetic disorder manifested by abnormal accumulation of unesterified cholesterol and other lipids. We screened combinatorially synthesized chemical libraries to identify compounds that would partially revert cholesterol accumulation. Cultured CHO cells with NPC phenotypes (CT60 and CT43) were used for screening along with normal CHO cells as a control. We developed an automated microscopy assay based on imaging of filipin fluorescence for estimating cholesterol accumulation in lysosomal storage organelles. Our primary screen of 14,956 compounds identified 14 hit compounds that caused significant reduction in cellular cholesterol accumulation at 10 microM. We then screened a secondary library of 3,962 compounds selected based on chemical similarity to the initial hits and identified 7 compounds that demonstrated greater efficacy and lower toxicity than the original hits. These compounds are effective at concentrations of 123 nM to 3 microM in reducing the cholesterol accumulation in cells with a NPC1 phenotype.
Highlights
Niemann-Pick disease type C (NPC) is an autosomal recessive genetic disorder manifested by abnormal accumulation of unesterified cholesterol and other lipids
We developed assays for correction of the NPC phenotype in CHO cell lines using filipin, which binds to nonesterified cholesterol and has been used to visualize the free cholesterol (FC) content in NPC cells
It can be seen that the CT60 cells show much more filipin staining than control cells and that the fluorescence in CT60 cells is concentrated in perinuclear lysosome-like storage organelle (LSO) organelles
Summary
Niemann-Pick disease type C (NPC) is an autosomal recessive genetic disorder manifested by abnormal accumulation of unesterified cholesterol and other lipids. We screened a secondary library of 3,962 compounds selected based on chemical similarity to the initial hits and identified 7 compounds that demonstrated greater efficacy and lower toxicity than the original hits. These compounds are effective at concentrations of 123 nM to 3 MM in reducing the cholesterol accumulation in cells with a NPC1 phenotype.—Pipalia, N. Niemann-Pick disease type C (NPC) is an autosomal recessive genetic disorder that causes an abnormal accumulation of cholesterol and other lipids in many cell types [1, 2].
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