Methods of determining efficacy of cyclodextrin therapy
Inventors
Ory, Daniel S • Porter, Forbes
Assignees
Washington University in St Louis WUSTL • National Institutes of Health NIH
Publication Number
US-9012216-B2
Publication Date
2015-04-21
Expiration Date
2029-04-10
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Abstract
Disclosed are methods for determining efficacy of a cyclodextrin therapy in a subject afflicted with a disorder involving oxysterol accumulation. These methods comprise: obtaining a first body fluid sample from the subject prior to cyclodextrin administration; administering cyclodextrin; obtaining at least one second body fluid sample after the cyclodextrin administration; subjecting the body fluid samples to chromatography-mass spectroscopy analysis to determine concentration of 24-hydroxycholesterol and/or cholestane-3β,5α,6β-triol; and determining magnitude of difference between the 24-hydroxycholesterol and/or cholestane-3β,5α,6β-triol concentration of the body fluid samples, whereby an increase or stabilization of 24-hydroxycholesterol concentration, or a reduction of cholestane-3β,5α,6β-triol concentration in the at least one second sample compared to the first sample, indicates efficacy of the cyclodextrin therapy.
Core Innovation
The invention provides methods for determining the efficacy of cyclodextrin therapy in subjects afflicted with disorders involving oxysterol accumulation, such as Niemann-Pick C (NPC) disease. These methods involve obtaining body fluid samples from the subject before and after cyclodextrin administration, analyzing the samples via chromatography-mass spectroscopy to measure concentrations of specific oxysterols—24-hydroxycholesterol and/or cholestane-3β,5α,6β-triol—and determining the difference in concentrations. An increase or stabilization in 24-hydroxycholesterol concentration or a reduction in cholestane-3β,5α,6β-triol concentration after treatment indicates efficacy of the therapy.
The problem addressed by this invention arises from challenges in diagnosing and monitoring NPC disease and other disorders involving oxysterol accumulation, due to the lack of widely available diagnostic tests and biomarkers that correlate with disease severity. This has led to delays in diagnosis and difficulties in evaluating therapeutic efficacy. The invention overcomes these obstacles by identifying specific oxysterols as biomarkers whose concentrations in body fluids can be quantitatively measured and used to assess disease presence, progression, and response to treatment.
The invention also establishes that oxysterol biomarkers, including 24-hydroxycholesterol, 7-ketocholesterol, and cholestane-3β,5α,6β-triol, can serve in screening, diagnosing, and monitoring disorders such as NPC disease. The methods provide protocols for extracting and quantifying these oxysterols from biological samples using chromatography and mass spectrometry, enabling rapid, accurate, and potentially high-throughput assessment. Monitoring changes in biomarker levels during and after cyclodextrin therapy offers a direct measure of treatment efficacy.
Claims Coverage
The patent includes two independent methods covering determination of therapy efficacy based on specific oxysterol concentration changes before and after cyclodextrin treatment in subjects with oxysterol accumulation disorders.
Determining efficacy by measuring 24-hydroxycholesterol concentration changes
A method involving obtaining body fluid samples before and after cyclodextrin administration, performing chromatography-mass spectroscopy analysis on the samples to determine 24-hydroxycholesterol concentration, and assessing efficacy by detecting an increase or stabilization of 24-hydroxycholesterol concentration in the post-treatment sample.
Determining efficacy by measuring cholestane-3β,5α,6β-triol concentration changes
A method involving obtaining body fluid samples before and after cyclodextrin administration, performing chromatography-mass spectroscopy analysis to determine cholestane-3β,5α,6β-triol concentration, and determining efficacy based on a reduction of cholestane-3β,5α,6β-triol concentration in the post-treatment sample compared to the pre-treatment sample.
The independent claims disclose methods for evaluating cyclodextrin therapy efficacy by quantifying specific oxysterol levels—either 24-hydroxycholesterol or cholestane-3β,5α,6β-triol—in body fluid samples collected before and after treatment, with specific concentration changes indicating effective therapy.
Stated Advantages
Provides a quantitative biomarker-based method to assess the efficacy of cyclodextrin therapy in disorders involving oxysterol accumulation.
Enables earlier and more accurate monitoring of treatment response in subjects with NPC disease.
Utilizes non-invasive or minimally invasive body fluid sampling combined with chromatography-mass spectroscopy for precise oxysterol quantification.
Allows differentiation between effective and ineffective therapy by measuring specific changes in oxysterol biomarkers.
Documented Applications
Screening and diagnosing subjects, including neonates, for Niemann-Pick C disease and other disorders involving oxysterol accumulation.
Monitoring disease progression and clinical status of subjects diagnosed with NPC disease.
Evaluating the efficacy of therapeutic treatments, including cyclodextrin therapy, by measuring oxysterol biomarker levels pre- and post-treatment.
Differentiating NPC disease from other lysosomal storage and cholesterol trafficking disorders.
Part of neonatal screening programs using high-throughput methods to identify affected subjects early.
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