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Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling.
- Source :
-
Journal of lipid research [J Lipid Res] 2013 Oct; Vol. 54 (10), pp. 2800-14. Date of Electronic Publication: 2013 Jul 23. - Publication Year :
- 2013
-
Abstract
- Niemann-Pick type C (NPC)1 is a rare neurodegenerative disease for which treatment options are limited. A major barrier to development of effective treatments has been the lack of validated biomarkers to monitor disease progression or serve as outcome measures in clinical trials. Using targeted metabolomics to exploit the complex lipid storage phenotype that is the hallmark of NPC1 disease, we broadly surveyed Npc1(-/-) mouse tissues and identified elevated species across multiple sphingolipid classes that increased with disease progression. There was a striking accumulation of sphingoid bases, monohexosylceramides (MCs), and GM2 gangliosides in liver, and sphingoid bases and GM2 and GM3 gangliosides in brain. These lipids were modestly decreased following miglustat treatment, but markedly decreased in response to treatment with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), two drugs that have shown efficacy in NPC1 animal models. Extending these studies to human subjects led to identification of sphingolipid classes that were significantly altered in the plasma of NPC1 patients. Plasma MCs and ceramides were elevated, whereas sphingoid bases were reduced in NPC1 subjects. Intervention with miglustat in NPC1 patients was accompanied by striking alterations in plasma (reductions in GM1 and GM3 gangliosides) and cerebrospinal fluid (CSF) (increased MCs) sphingolipids. Similar alterations were observed in the CSF from the NPC1 feline model following HP-β-CD treatment. Our findings suggest that these lipid biomarkers may prove useful as outcome measures for monitoring efficacy of therapy in clinical trials.
- Subjects :
- 1-Deoxynojirimycin analogs & derivatives
1-Deoxynojirimycin pharmacology
1-Deoxynojirimycin therapeutic use
2-Hydroxypropyl-beta-cyclodextrin
Animals
Biomarkers blood
Biomarkers cerebrospinal fluid
Cats
Chromatography, High Pressure Liquid
Drug Evaluation, Preclinical
Female
Gangliosides blood
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Niemann-Pick Disease, Type C diagnosis
Niemann-Pick Disease, Type C drug therapy
Organ Specificity
Sphingolipids cerebrospinal fluid
Sulfoglycosphingolipids blood
Tandem Mass Spectrometry
beta-Cyclodextrins pharmacology
beta-Cyclodextrins therapeutic use
Niemann-Pick Disease, Type C blood
Sphingolipids blood
Subjects
Details
- Language :
- English
- ISSN :
- 1539-7262
- Volume :
- 54
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of lipid research
- Publication Type :
- Academic Journal
- Accession number :
- 23881911
- Full Text :
- https://doi.org/10.1194/jlr.M040618