Biomarkers for Niemann-pick C disease and related disorders
Inventors
Ory, Daniel S. • Porter, Forbes D.
Assignees
Washington University in St Louis WUSTL • National Institutes of Health NIH
Publication Number
US-8497122-B2
Publication Date
2013-07-30
Expiration Date
2029-04-10
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Abstract
Methods for screening or diagnosing subjects for disorders involving accumulation of one or more oxysterols such as cytotoxic oxysterol accumulation, Niemann-Pick C(NPC) disease, lysosomal storage diseases, cholesterol trafficking diseases, and neurodegenerative diseases. Also provided are methods for methods for screening or diagnosing subjects (including infants and neonatal subjects) for NPC disease, methods for monitoring the progression, remission, and clinical status of NPC disease, and methods for evaluating the efficacy of therapeutic treatment of NPC disease.
Core Innovation
The invention relates to the identification and use of certain oxysterols as biomarkers for disorders involving accumulation of oxysterols, such as Niemann-Pick C (NPC) disease, lysosomal storage diseases, cholesterol trafficking diseases, and neurodegenerative diseases. The invention provides methods for screening, diagnosing, monitoring progression, remission, and clinical status of NPC disease, as well as evaluating the efficacy of therapeutic treatments by quantifying oxysterol concentrations in biological samples obtained from subjects.
NPC disease is an autosomal recessive lysosomal storage and neurodegenerative disorder characterized by accumulation of cholesterol and other lipids in organs and the central nervous system, leading to neuronal damage and variable clinical phenotypes. Despite advances in genetics and biochemistry, diagnosis of NPC disease is often delayed by about five years due to lack of newborn screening, disease biomarkers, and widely available diagnostic tests. The absence of biomarkers has also hindered assessment of therapeutic efficacy for NPC disease.
Claims Coverage
The patent contains several independent claims that cover methods for diagnosing, monitoring, and evaluating Niemann-Pick C disease using oxysterol biomarkers.
Diagnosing Niemann-Pick C disease using oxysterol concentration
A method involving obtaining a body fluid sample from a subject, analyzing the sample by chromatography-mass spectrometry to determine concentrations of at least one oxysterol selected from 7-ketocholesterol and cholestane-3β,5α,6β-triol, comparing these concentrations to reference values from a control population, and diagnosing NPC disease if the concentration exceeds the reference value.
Quantification of oxysterols with internal standards
Determining oxysterol concentrations by adding a known amount of an oxysterol internal standard to the sample, extracting oxysterols, and quantifying them using chromatography procedures.
Matching control populations for diagnosis
Using control populations matched in age and/or sex to the subject for determining reference values in diagnostics, particularly emphasizing the use of average oxysterol concentrations from such matched control groups.
Neonatal screening via oxysterol analysis on screening cards
Methods for diagnosing NPC disease in neonatal subjects involving quantifying oxysterols from body fluid samples applied to neonatal screening cards, including addition of internal standards, extraction, quantification, and comparison to neonatal control reference values.
Determining disease status by monitoring oxysterol levels over time
Methods for monitoring NPC disease status by obtaining body fluid samples at different times, quantifying oxysterols selected from 24-hydroxycholesterol, 7-ketocholesterol, and cholestane-3β,5α,6β-triol and comparing them to prior values or control populations to assess disease progression or remission.
The independent claims focus on using specific oxysterols, particularly 7-ketocholesterol, cholestane-3β,5α,6β-triol, and 24-hydroxycholesterol, as biomarkers for NPC disease diagnosis, monitoring, neonatal screening, and treatment efficacy, employing chromatography-mass spectrometry and internal standard quantification methods comparing subject samples to matched reference populations.
Stated Advantages
Enables early and accurate screening and diagnosis of NPC disease, including in neonatal subjects.
Provides biomarkers that correlate with disease severity and progression, allowing monitoring of clinical status.
Facilitates evaluation of therapeutic efficacy through quantification of oxysterol levels during treatment.
Allows differentiation of NPC disease from other lysosomal storage diseases based on distinct oxysterol profiles.
Methods can be adapted for high throughput and automated screening, suitable for broad clinical and neonatal application.
Documented Applications
Screening and diagnosing subjects—including infants and neonates—for NPC disease and related disorders involving oxysterol accumulation.
Monitoring progression, remission, and clinical status of NPC disease in diagnosed patients.
Evaluating efficacy of therapeutic treatments for NPC disease by tracking changes in oxysterol biomarker levels.
Distinguishing NPC disease patients from those with other lysosomal storage diseases based on plasma oxysterol profiles.
Neonatal screening programs employing blood samples such as dried blood spots on neonatal screening cards for early detection of NPC disease.
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