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 lysosomes and endosomes, LDL-cholesterol transport from endocytic compartments to other cellular compartments is delayed, and LDL does not elicit normal homeostatic responses. 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 amphotericin B-mediated cytotoxicity assay to screen for potential therapeutic drugs that induce cholesterol movement in cultured NPC cells. NPC cells are relatively resistant to amphotericin 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 compounds was screened and 55 compounds were identified that promote amphotericin B-mediated killing of NPC cells.One compound, NP-27, corrected the NPC phenotype by four different measures of cholesterol homeostasis. In addition to making NPC cells more sensitive to amphotericin B, NP-27 stimulated two separate cholesterol transport pathways and restored LDL stimulation of cholesterol esterification to near normal levels. 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 lysosomes and endosomes, LDL-cholesterol transport from endocytic compartments to other cellular compartments is delayed, and LDL does not elicit normal homeostatic responses. 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 amphotericin B-mediated cytotoxicity assay to screen for potential therapeutic drugs that induce cholesterol movement in cultured NPC cells. NPC cells are relatively resistant to amphotericin 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 compounds was screened and 55 compounds were identified that promote amphotericin B-mediated killing of NPC cells. One compound, NP-27, corrected the NPC phenotype by four different measures of cholesterol homeostasis. In addition to making NPC cells more sensitive to amphotericin B, NP-27 stimulated two separate cholesterol transport pathways and restored LDL stimulation of cholesterol esterification to near normal levels. Niemann-Pick C (NPC) is an autosomal recessive lysosomal lipid storage disease (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.A. Carstea E. Neufeld E.B. Blanchette-Mackie J.E. Pentchev P.G. Niemann-Pick Disease Type C: a lipid trafficking disorder.in: Valle D. 8th edition. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. McGraw-Hill, New York2001: 3611-3633Google Scholar). Historically, NPC has been considered a disease of cholesterol metabolism, since a major lipid that is stored in visceral organs is cholesterol. However, in reality it is a complex lipid storage disorder, with increases in sphingomyelin, cholesterol, lysobisphosphatidic acid, neutral and acidic glycosphingolipids, and phospholipids seen in liver and spleen. The lipid storage pattern differs dramatically in the brain where gangliosides are the main storage material and cholesterol is stored to a lesser extent (2Zervas M. Dobrenis K. Walkley S.U. Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations.J. Neuropathol. Exp. Neurol. 2001; 60: 49-64Google Scholar). NPC patients exhibit progressive loss of motor skills, learning difficulties, dementia, and seizures (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.A. Carstea E. Neufeld E.B. Blanchette-Mackie J.E. Pentchev P.G. Niemann-Pick Disease Type C: a lipid trafficking disorder.in: Valle D. 8th edition. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. McGraw-Hill, New York2001: 3611-3633Google Scholar), all of which signal central nervous system degeneration. Onset of symptoms in the majority of NPC children is school age, and the disease is generally fatal within a decade. NPC disease is caused by mutations in one of two genetic loci, NPC1 (3Carstea E.D. Morris J.A. Coleman K.G. Loftus S.K. Zhang D. Cummings C. Gu J. Rosenfeld M.A. Pavan W.J. Krizman D.B. Nagle J. Polymeropoulos M.H. Sturley S.L. Ioannou Y.A. Higgins M.E. Comly M. Cooney A. Brown A. Kaneski C.R. Blanchette-Mackie E.J. Dwyer N.K. Neufeld E.B. Chang T.-Y. Liscum L. Strauss J.F. Ohno K. Zigler M. Carmi R. Sokol J. Markie D. O'Neill R.R. v. Diggelen O.P. Elleder M. Patterson M.C. Brady R.O. Vanier M.T. Pentchev P.G. Tagle D.A. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.Science. 1997; 277: 228-231Google Scholar) and NPC2 (4Naureckiene S. Sleat D.E. Lackland H. Fensom A. Vanier M.T. Wattiaux R. Jadot M. Lobel P. Identification of HE1 as the second gene of Niemann-Pick C disease.Science. 2000; 290: 2298-2301Google Scholar). NPC1 and NPC2 phenotypes are clinically and biochemically indistinguishable and the two genes may encode constituents of the same lipid transport pathway. The NPC1 gene product is a 1278 amino acid membrane protein found in late endosomes (5Watari H. Blanchette-Mackie E.J. Dwyer N.K. Glick J.M. Patel S. Neufeld E.B. Brady R.O. Pentchev P.G. Strauss 3rd, J.F. Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization.Proc. Natl. Acad. Sci. USA. 1999; 96: 805-810Google Scholar, 6Neufeld E.B. Wastney M. Patel S. Suresh S. Cooney A.M. Dwyer N.K. Roff C.F. Ohno K. Morris J.A. Carstea E.D. Incardona J.P. Strauss 3rd J.F. Vanier M.T. Patterson M.C. Brady R.O. Pentchev P.G. Blanchette-Mackie E.J. The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo.J. Biol. Chem. 1999; 274: 9627-9635Google Scholar, 7Higgins M.E. Davies J.P. Chen F.W. Ioannou Y.A. Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network.Mol. Genet. Metab. 1999; 68: 1-13Google Scholar). Mutations in NPC1 cause altered lipid transport kinetics and lysosomal accumulation of cholesterol and gangliosides (8Pentchev P.G. Blanchette-Mackie E.J. Liscum L. Biological implications of the Niemann-Pick C mutation.Subcellular Biochemistry. 1997; 28: 437-451Google Scholar, 9Liscum L. Niemann-Pick type C mutations cause lipid traffic jam.Traffic. 2000; 1: 218-225Google Scholar, 10Puri V. Watanabe R. Dominguez M. Sun X. Wheatley C.L. Marks D.L. Pagano R.E. Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid storage diseases.Nat. Cell Biol. 1999; 1: 386-388Google Scholar). The biological function of NPC1 still is not clear; however, recent evidence suggests that NPC1 may have a permease activity (11Davies J.P. Chen F.W. Ioannou Y.A. Transmembrane molecular pump activity of Niemann-Pick C1 protein.Science. 2000; 290: 2295-2298Google Scholar). Molecular cloning of NPC2 reveals that the protein is likely to be a soluble lysosomal protein with cholesterol binding activity (4Naureckiene S. Sleat D.E. Lackland H. Fensom A. Vanier M.T. Wattiaux R. Jadot M. Lobel P. Identification of HE1 as the second gene of Niemann-Pick C disease.Science. 2000; 290: 2298-2301Google Scholar). NPC disease does not affect lipoprotein levels or produce premature vascular disease. Thus, therapies that target hypercholesterolemia are not effective against NPC (12Erickson R.P. Garver W.S. Camargo F. Hossain G.S. Heidenreich R.A. Pharmacological and genetic modifications of somatic cholesterol do not substantially the of disease in Niemann-Pick C Metab. 2000; Scholar). and liver in NPC patients and an NPC mouse model have not the of neurological symptoms (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.A. Carstea E. Neufeld E.B. Blanchette-Mackie J.E. Pentchev P.G. Niemann-Pick Disease Type C: a lipid trafficking disorder.in: Valle D. 8th edition. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. McGraw-Hill, New York2001: 3611-3633Google Scholar). Currently, there is no therapy that the progressive that is seen in NPC a biological function for it is to a screen for therapeutic compounds that or the have developed and implemented an amphotericin B-mediated cytotoxicity assay to screen for potential therapeutic drugs that of the NPC B is a that in in and We found that cells with an NPC phenotype are resistant to amphotericin B-mediated N.K. M.A. Liscum L. and of cells in the intracellular of LDL-derived Biol. Chem. Scholar), due to lysosomal cholesterol storage in membrane cholesterol compounds that induce cholesterol movement from NPC a 44,240 library was screened for that cause amphotericin B-mediated killing in NPC cells. The screen has identified one that pathways of intracellular cholesterol transport in NPC cells. acid acid and were from was from was from other were from or from were from was from was from were from LDL was by S.K. Brown of lipoprotein in cultured Scholar). was as the S.K. Brown of lipoprotein in cultured Scholar). The were of and with and and in which the was with or is with a or to cholesterol and the cholesterol pathway the of and and NPC mouse ovarian granulosa cells were by F. Strauss of and Pentchev of and of NPC cells were from the npc nih mouse model S.K. Morris J.A. Carstea E.D. Gu Cummings C. Brown A. J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. model of Niemann-Pick C in a cholesterol 1997; 277: Scholar). were in a in in a were with and compounds identified in were in and to the a of were and as in the Cell was using a assay assay for cellular and to and cytotoxicity Scholar, S. A. M. assay and neutral in the of the potential of Sci. Scholar) as A. Liscum L. for a cholesterol transport pathway from lysosomes to that is of the Biol. Chem. Scholar). NPC cells were in cells were with the compounds were to in a of in were in the two of the cells were with and with or amphotericin cells were with and was using a were with the was and for was by the were cultured and with as in the to and and were as L. lipoprotein of cholesterol and LDL is in Niemann-Pick type C Biol. Chem. Scholar). were the were in and for protein with the Biol. Chem. Scholar). for was by as an the of cellular normal and NPC cells were in in cells were cells were with or NP-27 or was and the cells were for were and the cellular of and was as are as the of cellular to and are the of four with cells were in in The cells were with and cells were with or LDL and compounds and for NP-27 and cells were with for The cellular of was as The are as protein and of in a cells were in in The cells were with and cells were with or LDL and compounds and for NP-27 and cells were with for The cellular of was as The are as protein and of were cultured and with as in the to Cell were for with and with were by the addition of of in and for were with which the was to by addition of The was with and the was with and were by using with acid for was by and acid as an the acid in normal and NPC of cells were in in cells were cells were and compounds were and for NP-27 and of was cells were and the cellular of was as in The are as a of the which were and for normal and NPC The the of in a cells were in in cells were cells were and compounds were and for NP-27 and of was cells were and the cellular of was as in The are as a of the which were and for normal and NPC The the of were cultured and with as in the to was as L. The intracellular transport of cholesterol is in Niemann-Pick Type C Cell Biol. Scholar), that was using for was by as an the The with however, be by and are to as in normal and NPC of cells were in in cells were cells were and compounds were and for NP-27, and of was cells were cellular were and to and the cellular of was as in The are as a of the which were and for normal and NPC The the of four in a cells were in in cells were cells were and compounds were and for NP-27, and of was cells were cellular were and to and the cellular of was as in The are as a of the which were and for normal and NPC The the of four were cultured and with as in the to were and and were and as A. Liscum L. for a cholesterol transport pathway from lysosomes to that is of the Biol. Chem. Scholar). were cultured and with LDL that is with as in the to were with cholesterol using the of J.P. S. S. of cholesterol and the and the Scholar). were were and and as Liscum L. of of intracellular cholesterol Scholar). were using a or The of was to compounds that the disease phenotype of cultured NPC cells. the biological function of NPC1 is were to a screen for compounds that a likely of NPC1 cholesterol transport from lysosomes to other cellular The screen for compounds an model for NPC disease and a assay that be for The that were simian virus 40-transformed mouse ovarian granulosa from and npc nih A. D. D. R. H. Strauss J.F. J. Biol. Scholar, Carstea E.D. Cummings C. Morris J.A. Loftus S.K. Zhang D. Coleman K.G. Cooney A.M. Comly M.E. L. Roff C. Tagle D.A. Pavan W.J. Pentchev P.G. Rosenfeld M.A. of the Niemann-Pick C by Natl. Acad. Sci. USA. 1997; Scholar). The NPC1 gene in npc nih has a that to NPC1 protein of amino S.K. Morris J.A. Carstea E.D. Gu Cummings C. Brown A. J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. model of Niemann-Pick C in a cholesterol 1997; 277: Scholar). The model a and phenotype the of the human disease and has a life span (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.A. Carstea E. Neufeld E.B. Blanchette-Mackie J.E. Pentchev P.G. Niemann-Pick Disease Type C: a lipid trafficking disorder.in: Valle D. 8th edition. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. McGraw-Hill, New York2001: 3611-3633Google Scholar, S.K. Morris J.A. Carstea E.D. Gu Cummings C. Brown A. J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. model of Niemann-Pick C in a cholesterol 1997; 277: Scholar, R. Neufeld E.B. Pentchev P.G. Vanier M.T. Suzuki K. of storage does not the of the Niemann-Pick C disease Genet. 2000; Scholar). cultured from the npc nih mouse have the cholesterol storage and movement of cholesterol to cholesterol in the that is seen in human NPC P.G. Comly M.E. Patel S. M. H. The cholesterol storage of the A genetic linked to esterification of cholesterol and to human type C Niemann-Pick Biol. Chem. Scholar). amphotericin B cytotoxicity assay was to NPC cells that the disease phenotype and that have cholesterol restored by the of a as amphotericin B and complex with and cells that have a of membrane in A and of Natl. Acad. Sci. USA. Scholar, K. H. S. M. and of amphotericin in Scholar). The the cytotoxicity assay is in cells in a cholesterol for are relatively resistant to amphotericin B the cholesterol of the membrane is LDL is to normal are in The cholesterol is to the membrane and the cells amphotericin B sensitive M. J. M. D. B of cells with in the of lipoprotein and cholesterol Natl. Acad. Sci. USA. Scholar). However, NPC cells amphotericin B LDL-cholesterol transport to the membrane is N.K. M.A. Liscum L. and of cells in the intracellular of LDL-derived Biol. Chem. Scholar). was to compounds that promote the movement of to the NPC cells amphotericin B We amphotericin B to be a with which to amphotericin B killing of normal and NPC cells is in In normal and NPC cells were cultured for in in the of cholesterol and an cholesterol the membrane cholesterol of in is for amphotericin B of cultured cells N.K. M.A. Liscum L. and of cells in the intracellular of LDL-derived Biol. Chem. however, to the were with or cells were or with amphotericin Cell was using a cells in were by amphotericin B not for in to amphotericin B of normal cells the addition of LDL caused amphotericin B NPC cells amphotericin B LDL of LDL amphotericin B were to amphotericin B to NPC cells not screen was to compounds that transport to the membrane in NPC cause amphotericin B compounds from a were for a of 44,240 The compounds were to all amphotericin B-mediated killing in the of compounds was with killing in the of compounds and in the of amphotericin A the of the is in The for the screen of compounds was and of the compounds that in the of cells were in the compounds were from to and were The amphotericin B-mediated killing of NPC cells in the of was with amphotericin B-mediated killing of normal as a of the killing that in The for NP-27, one of the compounds identified in the is in of NP-27 amphotericin B killing in the cells were in in cells were with was from to in cells were with and with or amphotericin cells were with and was using a assay as The are as of cells using a that the amphotericin B-mediated killing of NPC cells in the of NP-27 with the amphotericin B-mediated killing of normal cells for the of the to the normal The was using the and the was the of The screen in the of 55 compounds that caused amphotericin B-mediated NPC with from to compounds were not were of the other compounds to of the NPC cholesterol levels are within a in normal cells by of cholesterol and the LDL A pathway that the cholesterol of and Natl. Acad. Sci. USA. 1999; 96: Scholar), as well as by of an that the esterification of a acid to cholesterol for storage in lipid Chang D. 1997; Scholar). NPC cells no of activity cellular cholesterol levels are by the addition of LDL (8Pentchev P.G. Blanchette-Mackie E.J. Liscum L. Biological implications of the Niemann-Pick C mutation.Subcellular Biochemistry. 1997; 28: 437-451Google Scholar, P.G. Brady R.O. Blanchette-Mackie E.J. Vanier M.T. Carstea E.D. E. Roff C.F. The Niemann-Pick C and to the intracellular and of LDL Scholar). is for NPC disease (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.A. Carstea E. Neufeld E.B. Blanchette-Mackie J.E. Pentchev P.G. Niemann-Pick Disease Type C: a lipid trafficking disorder.in: Valle D. 8th edition. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. McGraw-Hill, New York2001: 3611-3633Google Scholar) and has been to in intracellular cholesterol transport L. Niemann-Pick type C mutations cause lipid traffic jam.Traffic. 2000; 1: 218-225Google Scholar, L. Niemann-Pick disease type Scholar). The of compounds and cholesterol esterification was in normal and NPC cells. compounds were by the movement of cellular cholesterol or LDL-derived cholesterol, the of to be of the compounds no cholesterol however, compounds cholesterol no cholesterol esterification the to LDL in normal cells which was in the amphotericin B no cholesterol esterification in NPC cells. compounds out in NP-27 and NP-27 stimulated cholesterol esterification in normal cells of NP-27 stimulated esterification in NPC cells and the in the cells to that of normal cells. of NP-27 were a of cholesterol esterification in NPC cells not in normal cells compounds cause cholesterol esterification by the However, found that NP-27 and no in activity in liver not compounds may to cholesterol esterification due to an acid metabolism, acid or a acid the cellular acid and the activity of not be as in and However, that NP-27 and not In NP-27 and a stimulation of acid the of cholesterol esterification and seen with compounds is not to an of acid NP-27 and a stimulation of an acid for the stimulation of cholesterol NP-27 to cholesterol esterification by and LDL-derived cholesterol to the to promote movement of LDL-derived cholesterol. compounds NP-27 and One by which compounds affect activity is by cholesterol is by cholesterol D. Chang Chang of by cholesterol or by in a Biol. Chem. Scholar) and have found that of cholesterol the of LDL to cholesterol esterification L. The intracellular transport of cholesterol is in cells cultured with Biol. Chem. Scholar). a that cholesterol may cholesterol However, that NP-27, and no cellular cholesterol in NPC promote the of stored lysosomal cholesterol. We the of compounds the movement of membrane cholesterol to in the cells with a of A. Liscum L. for a cholesterol transport pathway from lysosomes to that is of the Biol. Chem. Scholar). and NPC cells were for with of along with compounds the the cells the and it to the cellular cholesterol of the cholesterol been to of the compounds an in normal cells. However, NP-27 stimulated to in NPC cells no in We the of compounds the movement of LDL-derived from lysosomes to the and NPC cells were for with in the and of NP-27 and The of LDL-derived that is to an cholesterol was as a of movement to the membrane A. Liscum L. for a cholesterol transport pathway from lysosomes to that is of the Biol. Chem. Scholar, J.P. S. S. of cholesterol and the and the Scholar, Liscum L. of of intracellular cholesterol Scholar). normal cells were with for of the LDL-derived was of the was in NPC cells NP-27 assay in normal cells not However, NP-27 the of the NPC membrane to to that of normal no NP-27 stimulated two separate pathways of intracellular cholesterol transport in NPC not in normal cells. The kinetics of cholesterol movement from lysosomes to membrane in NPC cells L. The intracellular transport of cholesterol is in Niemann-Pick Type C Cell Biol. Scholar, Comly M.E. Blanchette-Mackie J. E. Kaneski C. Vanier M.T. Brady R.O. Pentchev P.G. Type C Niemann-Pick cellular of cholesterol is linked to the of in the intracellular transport of Scholar, E.B. Cooney A.M. J. Dwyer N.K. Pentchev P.G. Blanchette-Mackie E.J. trafficking of cholesterol with a Biol. Chem. Scholar) in lysosomal storage of cholesterol, which be by is a that to cholesterol and is to cellular cholesterol E.J. Dwyer N.K. Sokol J. Comly M.E. Vanier M.T. Brady R.O. Pentchev P.G. Niemann-Pick lipoprotein is with premature cholesterol accumulation in the complex and cholesterol storage in Natl. Acad. Sci. USA. Scholar). cells cultured in the membrane and in a likely endosomes and NPC cells the of human NPC not that cholesterol movement by NPC1 function cause of stored cholesterol, compounds that of NPC1 may have no We the of compounds to the stored cholesterol by the NPC cells for in LDL and Cholesterol storage was by of as K. D. M. Liscum L. of a with of cholesterol from the membrane to the 1997; Scholar). to no of We with compounds and found that with compounds or to The of NP-27 and is in In normal cells were for in of NP-27 caused caused to with compounds in no of stored cholesterol, as by of cells. were in with and LDL not NP-27 was identified in a screen for compounds that the phenotype of cultured NPC cells. In normal cultured of the that is from lysosomes is to the from there it the However, NPC cells exhibit movement of out of lysosomes and lysosomal storage of cholesterol, which is of NPC disease. In found that NP-27 corrected the NPC phenotype using four different measures of cholesterol NPC cells with NP-27 were more sensitive to killing by amphotericin B, NPC cells cholesterol esterification and near normal of cholesterol NP-27 restored LDL-cholesterol movement from lysosomes to the membrane in NPC and NP-27 stimulated membrane cholesterol movement to the in NPC cells. The that NP-27 stimulated esterification that the the movement of cellular cholesterol as well as LDL-derived cholesterol. NP-27 is a that is and In cultured the target of NP-27 is The is not likely to since NPC cells were from the npc nih mouse which a NPC1 NP-27 does not promote cholesterol from since the no cholesterol transport pathways in normal cells. are with a of lysosomal cholesterol in NPC which amphotericin B of NPC cells and however, the of NP-27 has to of stored lysosomal cholesterol. may be due to the of the The transport are of in the kinetics of cholesterol a major in lysosomal cholesterol may have to for by NPC disease is caused by mutations in NPC1 or NPC2 with NPC exhibit a and progressive loss of motor skills, learning dementia, and all of which signal central nervous system (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.A. Carstea E. Neufeld E.B. Blanchette-Mackie J.E. Pentchev P.G. Niemann-Pick Disease Type C: a lipid trafficking disorder.in: Valle D. 8th edition. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. McGraw-Hill, New York2001: 3611-3633Google Scholar). NPC children have an liver and which has in the disease is one in (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.A. Carstea E. Neufeld E.B. Blanchette-Mackie J.E. Pentchev P.G. Niemann-Pick Disease Type C: a lipid trafficking disorder.in: Valle D. 8th edition. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. McGraw-Hill, New York2001: 3611-3633Google Scholar). Onset of neurological symptoms is in and generally Currently, there is no therapy for NPC disease. NPC does not affect lipoprotein levels or cause vascular disease. therapies that target cholesterol have been in NPC mouse and NPC children. (12Erickson R.P. Garver W.S. Camargo F. Hossain G.S. Heidenreich R.A. Pharmacological and genetic modifications of somatic cholesterol do not substantially the of disease in Niemann-Pick C Metab. 2000; Scholar) and the npc nih mouse drugs to a in liver unesterified cholesterol and liver cholesterol, there was no of disease of a in the gene to npc nih no the onset of neurological symptoms (12Erickson R.P. Garver W.S. Camargo F. Hossain G.S. Heidenreich R.A. Pharmacological and genetic modifications of somatic cholesterol do not substantially the of disease in Niemann-Pick C Metab. 2000; Scholar). Patterson and found that of NPC children with and acid in a of cholesterol and unesterified cholesterol M.C. A.M. Higgins R. R.P. K. Pentchev P.G. The of and cholesterol in Niemann-Pick disease type however, found no in the of the disease (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.A. Carstea E. Neufeld E.B. Blanchette-Mackie J.E. Pentchev P.G. Niemann-Pick Disease Type C: a lipid trafficking disorder.in: Valle D. 8th edition. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. McGraw-Hill, New York2001: 3611-3633Google Scholar). were human liver R. S. of storage disease with liver Scholar), in the mouse model of NPC M. M. K. S. for Niemann-Pick Scholar), and and liver in the mouse model R. S. K. R.A. S. in the an model of Niemann-Pick Scholar). that the visceral disease is not to be a therapy for NPC the One found to onset of neurological symptoms and life span of npc nih was with an of M. M.A. Walkley S.U. for in Niemann-Pick disease type Biol. 2001; Scholar). that accumulation a in the of NPC disease. A of NP-27 be in the NPC mouse is by the that the all of NP-27, which are to cultured cells. the of of compounds NPC disease a NP-27 that is the activity within the of compounds to the of was by to and from the was by the of Cell was by the for and The and for The and for the as well as New the with the in LDL with Niemann-Pick disease type C
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