Niemann-Pick type C1 (NPC1) disease is a rare, progressive neurodegenerative disorder characterized by accumulation of cholesterol and other lipids in the viscera and central nervous system. A barrier to the development of treatments for NPC1 disease is the lack of readily quantifiable outcome measures to evaluate efficacy of therapy in clinical trials. Through broad-based metabolomic efforts, we have discovered in NPC1 subjects cholesterol oxidation product (oxysterol) biomarkers that reflect the unique intersection of oxidative stress and unesterified cholesterol storage - the biochemical hallmark of NPC1 disease. This proposal tests the highly innovative hypothesis that oxysterol biomarkers, together with other cholesterol homeostatic markers, can serve as outcome measures to assess the effect of disease-modifying therapies (e.g., 2-hydroxypropyl-?-cyclodextrin, HP-?-CD) on cholesterol metabolism in the CNS and to monitor disease progression. 24(S)-HC, which is synthesized almost exclusively in large neurons in the CNS, and CSF cholesteryl esters (CE) offer potential quantitative, non-invasive metrics to guide dosing and to monitor drug response. Likewise, cholestane-3?, 5?, 6?-triol (triol), which we have previously shown to be elevated in the CSF of NPC1 subjects, will inform with respect to the effect of HP-?-CD on intraneuronal cholesterol storage. This hypothesis will be tested in NPC1 animal models administered intracerebroventricular (ICV) HP-?-CD (Aim 1), and in NPC1 human subjects enrolled in a natural history study and in a Phase 1 trial for ICV HP-?-CD at the NIH Clinical Center (Aim 2). The proposal will also explore the possibility that the exceptional receiver operating characteristics (ROC) of the triol assay can be harnessed to develop a newborn screen to identify NPC1 patients earlier and thus intervene in pre-symptomatic patients (Aim 3). The proposed newborn screen for NPC1 disease is innovative and would be the first for a non-enzymatic lysosomal disorder, as well as the first for an inborn error of sterol metabolism. While the goal of this project is to develop a prototype newborn screen for NPC1 disease suitable for implementation at the statewide or regional level, the tandem mass spectrometry methods developed for extraction and detection of the oxysterols could be readily extended to metabolites that accumulate in other sterol disorders (e.g., Smith-Lemli-Opitz Syndrome), thereby permitting multiplexed screening for several inherited disorders within the context of a single screen. The studies in this proposal are highly significant because we address the critical unmet therapeutic and diagnostic needs of NPC1 disease.

Public Health Relevance

Niemann-Pick type C1 (NPC1) disease is a rare neurodegenerative disorder characterized by accumulation of cholesterol and other lipids in the brain and other organs. Children affected by the disease show symptoms in early childhood, experience progressive impairment of motor and intellectual function, and usually die in adolescence. NPC1 disease is extraordinarily difficult to diagnose, and there are no FDA-approved therapies for this disorder. A barrier to the development of therapies for NPC1 disease is the lack of outcome measures for clinical trials. The goals of this project are to test whether new biochemical markers ('biomarkers') can be used to evaluate therapies and whether these biomarkers can be used to screen newborns for NPC1 disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
4R01NS081985-04
Application #
9069134
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Morris, Jill A
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jiang, Xuntian; Sidhu, Rohini; Orsini, Joseph J et al. (2018) Diagnosis of niemann-pick C1 by measurement of bile acid biomarkers in archived newborn dried blood spots. Mol Genet Metab :
Berry-Kravis, Elizabeth; Chin, Jamie; Hoffmann, Anne et al. (2018) Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-?-Cyclodextrin. Pediatr Neurol 80:24-34
Li, Rong; Hao, Jon; Fujiwara, Hideji et al. (2017) Analytical Characterization of Methyl-?-Cyclodextrin for Pharmacological Activity to Reduce Lysosomal Cholesterol Accumulation in Niemann-Pick Disease Type C1 Cells. Assay Drug Dev Technol 15:154-166
Gray-Edwards, Heather L; Jiang, Xuntian; Randle, Ashley N et al. (2017) Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy. Mol Ther Methods Clin Dev 6:135-142
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Ory, Daniel S; Ottinger, Elizabeth A; Farhat, Nicole Yanjanin et al. (2017) Intrathecal 2-hydroxypropyl-?-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet 390:1758-1768
Tayebi, Nahid; Parisiadou, Loukia; Berhe, Bahafta et al. (2017) Glucocerebrosidase haploinsufficiency in A53T ?-synuclein mice impacts disease onset and course. Mol Genet Metab 122:198-208
Jiang, Xuntian; Ory, Daniel S (2016) Towards a New Diagnostic Standard for Niemann-Pick C Disease. EBioMedicine 4:18-9
Jiang, Xuntian; Sidhu, Rohini; Mydock-McGrane, Laurel et al. (2016) Development of a bile acid-based newborn screen for Niemann-Pick disease type C. Sci Transl Med 8:337ra63
Sidhu, Rohini; Jiang, Hui; Farhat, Nicole Y et al. (2015) A validated LC-MS/MS assay for quantification of 24(S)-hydroxycholesterol in plasma and cerebrospinal fluid. J Lipid Res 56:1222-33

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