Decoding cerebrospinal fluid huntingtin biomarkers

解码脑脊液亨廷顿生物标志物

• 批准号: 10614938
• 负责人: Amber L Southwell
• 金额: $ 41.1万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614938
• 关键词: Active Biological Transport; Acute Brain Injuries; Address; Alleles; Antisense Oligonucleotides; Basal Ganglia; Biological Markers; Blood; Brain; Brain region; British Columbia; Cell physiology; Cells; Cerebrospinal Fluid; Clinic; Clinical; Clinical Treatment; Clinical Trials; Collection; Complex; Data; Data Analyses; Development; Discrimination; Disease; Disease Progression; Dose; Eligibility Determination; Flow Cytometry; Goals; Health; Huntington Disease; Huntington gene; Immunoprecipitation; Individual; Intervention; Kinetics; Knowledge; Longitudinal Studies; Longitudinal cohort; Measurement; Measures; MicroRNAs; Monitor; Mus; Nerve Degeneration; Neurons; Onset of illness; Participant; Pathway interactions; Patients; Phase; Placebos; Plasma; Predictive Value; Proteins; Sampling; Source; Structure; System; Therapeutic; Time; Tissues; Universities; Viral Vector; Work; biobank; brain cell; cell type; clinical trial participant; detection assay; extracellular; glymphatic clearance; glymphatic system; injured; man; mutant; neuroprotection; novel; phenotypic data; pre-clinical; tool

PROJECT SUMMARY The goal of this project is to functionalize quantitation of cerebrospinal fluid (CSF) huntingtin (HTT) protein as a Huntington disease (HD) biomarker. The first Phase I/IIa HTT lowering clinical trial for the treatment of HD recently concluded demonstrating dose-dependent reduction of mutant HTT (mtHTT) protein in the CSF of treated patients. The use of this measure was based on our previous work using a novel ultrasensitive mtHTT detection assay to demonstrate that suppression of HTT in the entire mouse CNS results in correlative reduction of CSF mtHTT, but further studies are required for meaningful use of this measure in the clinic. The therapeutic under trial is expected to mostly be active in superficial brain regions, while other strategies in development are expected to mostly be active in deeper brain regions or specific cell types. For this reason, it is necessary to know the regional and cell type contributions to CSF mtHTT in order to predict what a treatment-induced change means for the targeted tissue(s). Comparison of brain and CSF mtHTT in mice that express mtHTT everywhere except the brain region or cell type at study to those with ubiquitous mtHTT expression will be used to discern the proportional contributions to CSF mtHTT and provide a way to infer magnitude of treatment-induced changes in the brain by those in CSF. It will also be necessary to know how mtHTT enters CSF. Comparison of brain and CSF HTT in systems with and without neurodegeneration will be used to distinguish passive release of HTT as cells die and break open from active transport of HTT to CSF. Furthermore, the kinetics of brain clearance of mtHTT will be delineated by ectopic delivery of intra- or extracellular mtHTT protein directly to the brains of mice and subsequent measurement of brain, CSF, and plasma mtHTT at multiple post-delivery time points. Perturbation of HTT secretion and the glymphatic system will be used to investigate how mtHTT moves from inside cells of the brain to the CSF and eventually the blood. Concurrently, mtHTT will be quantified in longitudinal CSF and plasma samples from HD patients and controls and compared to phenotypic data to determine how biofluid mtHTT changes over typical clinical trial intervals and with progression in individuals, thus separating time- and treatment-dependent changes. This will also determine if CSF mtHTT concentration can be used to more accurately predict disease conversion and progression. We will also attempt to quantify wtHTT protein in CSF to investigate potential extracellular functions of HTT as well as enable allelic discrimination for trials of selective agents. The results of these studies will provide the necessary basis to interpret clinical quantitation of CSF HTT, determine which types of therapeutics could be effectively evaluated by this measure, and ascertain the predictive value of longitudinal CSF HTT quantitation in monitoring HD progression and selecting clinical trial participants.

项目摘要 本项目的目标是将脑脊液（CSF）亨廷顿（HTT）蛋白定量功能化， 亨廷顿病（HD）生物标志物。首个用于治疗HD的I/IIa期降低HTT临床试验 最近得出的结论表明，剂量依赖性减少突变HTT（mtHTT）蛋白在CSF中的 治疗的病人。这种措施的使用是基于我们以前的工作，使用一种新的超灵敏mtHTT 检测分析以证明在整个小鼠CNS中抑制HTT导致相关的降低 的CSF mtHTT，但需要进一步的研究，在临床上有意义的使用这一措施。治疗 正在试验中的，预计主要是活跃在大脑表层区域，而其他发展中的战略， 预计主要活跃于大脑深部区域或特定细胞类型。为此，有必要 了解区域和细胞类型对CSF mtHTT的贡献，以便预测治疗引起的变化 用于靶组织的装置。在各处表达mtHTT的小鼠中比较脑和CSF mtHTT 除了研究中的脑区域或细胞类型与那些具有普遍存在的mtHTT表达的区域或细胞类型之外， 对CSF mtHTT的比例贡献，并提供了一种推断治疗诱导变化幅度的方法 在脑内的分布还需要了解mtHTT如何进入CSF。大脑与 具有和不具有神经变性的系统中的CSF HTT将用于区分HTT的被动释放， 细胞因HTT主动转运至CSF而死亡和破裂。此外，脑清除的动力学 mtHTT将通过将细胞内或细胞外mtHTT蛋白直接异位递送至小鼠大脑来描述 以及随后在多个分娩后时间点测量脑、CSF和血浆mtHTT。 HTT分泌和胶质淋巴系统的扰动将用于研究mtHTT如何从 从脑细胞到脑脊液最终到血液同时，将纵向量化mtHTT HD患者和对照的CSF和血浆样本，并与表型数据进行比较，以确定 生物流体mtHTT在典型的临床试验间隔内变化，并随着个体的进展而变化，从而将 时间和治疗依赖性变化。这也将确定CSF mtHTT浓度是否可用于 更准确地预测疾病的转化和进展。我们还将尝试定量WtHTT蛋白， CSF，以研究HTT的潜在细胞外功能，并使等位基因区分试验 选择剂。这些研究的结果将提供必要的基础，以解释临床定量的 CSF HTT，确定哪种类型的治疗方法可以有效地评估这一措施，并确定 纵向CSF HTT定量在监测HD进展和选择临床试验中预测价值 参与者