OXYSTEROL BIOMARKERS FOR NIEMANN-PICK C DISEASE

尼曼-皮克 C 病的氧甾醇生物标志物

基本信息

批准号：
8658869
负责人：
DANIEL S ORY
金额：
$ 26.33万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658869
关键词：
7-ketocholesterol Address Adolescence Affect Anabolism Animal Model Area Under Curve Binding Biochemical Biochemical Markers Biological Assay Biological Markers Blood Blood Tests Blood specimen Brain Child Cholestanes Cholesterol Cholesterol Esters Cholesterol Homeostasis Clinical Clinical Trials Clinical Trials Design Complex Cyclodextrins Detection Development Diagnosis Diagnostic Disease Disease Progression Dose Drug Approval Processes Drug Kinetics Drug Monitoring Endoplasmic Reticulum Enrollment Esterification European FDA approved Felis catus Filipin Future Gangliosides Genes Glycosphingolipids Goals Human Hydroxycholesterols Inborn Genetic Diseases Incidence Individual Intervention Life Lipids Lipoproteins Liquid Chromatography Mediating Metabolism Methodology Methods Metric Miglustat Modeling Monitor Mus Mutation Natural History Neonatal Screening Neuraxis Neurodegenerative Disorders Neurons Nuclear Pore Complex Organ Outcome Measure Oxidative Stress Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Plasma Population Process Receiver Operating Characteristics Resources Running Sampling Smith-Lemli-Opitz Syndrome Spottings Staining method Stains Sterols Surveys Symptoms Testing Therapeutic Time Tissue Sample Treatment Efficacy United States National Institutes of Health Validation Viscera Work base cholesterol trafficking clinical efficacy cohort design early childhood experience human subject improved in vivo inhibitor/antagonist innovation metabolomics motor impairment oxidation prototype public health relevance response safety testing screening tandem mass spectrometry therapy development

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由适用提供）：Niemann-Pick型C1（NPC1）疾病是一种罕见的，进行性神经退行性疾病，其特征是内脏和中枢神经系统中胆固醇和其他脂质的积累。 NPC1疾病治疗的发展的障碍是缺乏在临床试验中评估治疗有效性的可量化结果指标。通过基于广泛的代谢组学努力，我们在NPC1受试者氧化胆固醇产物（“氧蛋白酶”）生物标志物中发现，反映了氧化应激和未酯化胆固醇储存的独特相交 - NPC1疾病的生化标志。该提案检验了高度创新的假设，即氧化酚生物标志物以及其他胆固醇稳态标记可以作为评估改良疾病改良疗法的影响（例如2-羟基丙基 - 丙基 - cyclodextrin，hp-cd-cd）对胆固醇的疾病的影响。 24（s）-HC几乎完全在中枢神经系统的大型神经元中合成，而CSF胆固醇酯（CE）提供了潜在的定量，非侵入性指标，以指导给药并监测药物反应。同样，我们先前证明在NPC1受试者CSF中升高的Cholestane -3，5¿，6¿ -Triol（“ Triol”）将涉及HP -cd对HP -CD对内神经元胆固醇储存的影响。该假设将在室内脑室内（ICV）HP -€-CD（AIM 1）的NPC1动物模型中进行检验，以及在NIH Clinical Center（AIM 2）的自然史研究和ICV HP -CD的NPC1人类受试者中。该提案还将探讨可以利用三醇测定法的特征（ROC）的特征（ROC）的可能性，以开发新生儿筛查以较早识别NPC1患者，从而干预症状前患者（AIM 3）。拟议的NPC1疾病的新生儿筛查具有创新性，并且将是第一个非酶溶酶体疾病的筛查，也是第一个出现固醇代谢的天生误差。 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单个屏幕的上下文。该提案中的研究非常重要，因为我们解决了NPC1疾病的关键未得到治疗和诊断需求。