OXYSTEROL BIOMARKERS FOR NIEMANN-PICK C DISEASE

尼曼-皮克 C 病的氧甾醇生物标志物

• 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
• 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

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（由申请人提供）：尼曼-匹克 C1 型（NPC1）疾病是一种罕见的进行性神经退行性疾病，其特征是胆固醇和其他脂质在内脏和中枢神经系统中积累。 NPC1 疾病治疗方法开发的一个障碍是缺乏易于量化的结果指标来评估临床试验中的治疗效果。通过广泛的代谢组学研究，我们在 NPC1 受试者中发现了胆固醇氧化产物（“氧甾醇”）生物标志物，这些生物标志物反映了氧化应激和未酯化胆固醇储存的独特交叉——NPC1 疾病的生化标志。该提案测试了高度创新的假设，即氧甾醇生物标志物与其他胆固醇稳态标志物一起可以作为结果指标，评估疾病缓解疗法（例如2-羟丙基-¿-环糊精、HP-¿-CD）对中枢神经系统胆固醇代谢的影响并监测疾病进展。 24(S)-HC 几乎完全在 CNS 的大神经元中合成，而 CSF 胆固醇酯 (CE) 提供了潜在的定量、非侵入性指标来指导给药和监测药物反应。同样，胆甾烷-3，5，6，三醇（“三醇”），我们之前已经证明其在 NPC1 受试者的 CSF 中升高，将告知 HP-K-CD 对神经元内胆固醇储存的影响。这一假设将在接受脑室内 (ICV) HP-¿-CD 的 NPC1 动物模型中进行测试（目标 1），并在 NIH 临床中心参加自然史研究和 ICV HP-¿-CD 一期试验的 NPC1 人类受试者中进行测试（目标 2）。该提案还将探讨利用三醇测定的特殊接受者操作特征 (ROC) 开发新生儿筛查的可能性，以更早识别 NPC1 患者，从而对出现症状的患者进行干预（目标 3）。拟议的 NPC1 疾病新生儿筛查具有创新性，将是第一个针对非酶溶酶体疾病的筛查，也是第一个针对先天性甾醇代谢错误的筛查。虽然该项目的目标是开发适合在全州或地区一级实施的 NPC1 疾病新生儿筛查原型，但为提取和检测氧甾醇而开发的串联质谱方法可以很容易地扩展到其他甾醇疾病（例如 Smith-Lemli-Opitz 综合征）中积累的代谢物，从而允许对多种遗传性疾病进行多重筛查。 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 疾病未满足的关键治疗和诊断需求。