Huntington's disease biomarkers and therapeutics

亨廷顿病的生物标志物和治疗方法

基本信息

批准号：
8915252
负责人：
Wenzhen Duan
金额：
$ 39.59万
依托单位：
JOHNS HOPKINS 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：
2013-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915252
关键词：
Agonist Biological Markers Brain Cell model Clinical Clinical Research Clinical Trials Corpus striatum structure Creatine Data Detection Development Disease Disease Progression Drug Kinetics Equilibrium Functional disorder Future Gene Mutation Glutamates Goals Huntington Disease Impairment Knock-in Mouse Length Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Medical Molecular Monitor Mus N-acetylaspartate Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Outcome Measure Pharmacodynamics Phase Research Structure-Activity Relationship Testing Therapeutic Therapeutic Agents Toxic effect Treatment Efficacy Validation analog base cerebral atrophy design efficacy trial functional disability gamma-Aminobutyric Acid human Huntingtin protein in vivo mouse model mutant neuroimaging neuronal circuitry pre-clinical preclinical efficacy preclinical study prevent protective effect public health relevance response small molecule

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a devastating neurodegenerative disorder caused by mutation of the gene huntingtin. No treatment prevented or slowed disease progression. To develop such a treatment requires objective measures of disease progression. Neuroimaging measures provide unbiased detection of disease progression. The key issues are whether these measures truly reflect the reduction or dysfunction of medium spiny neurons - the nerve cells that selectively die in HD, and whether the neuroimaging measures correlate with other clinical features; more important is whether these measures respond to treatment sensitively and reliably. We propose employing two non-invasive longitudinal neuroimaging measures reflecting different features of the neurons, in vivo structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), to determine if these measures provide the sensitive and faithful reflection of the therapeutic efficacy, and how these non-invasive measures correlate with mutant huntingtin-induced functional impairment in the full-length huntingtin knock-in mouse model. In Specific Aim 1, we will validate structural MRI measures as biomarkers and determine their response to neuroprotective treatment in full-length huntingtin knock-in mice. We will determine the correlation between MRI measures and functional impairment in HdhQ250 mice with or without treatment. In Specific Aim 2, we will investigate brain metabolite alterations in parallel with disease progression and determine whether these metabolites respond to neuroprotective treatment by use of magnetic resonance spectroscopy in full-length huntingtin knock-in mice. We hypothesize that alterations of striatal metabolites reflects early neuronal dysfunction and impairment of neuronal circuitry. We will determine if these altered metabolites respond to neuroprotective treatment, and what are the relationships between brain metabolite alterations and functional consequences of mutant huntingtin in the full- length huntingtin knock-in mice. In Specific Aim 3, we will identify clinical candidate small molecule TrkB agonist(s) by using HD cell models and further assess preclinical efficacy, pharmacokinetics, pharmacodynamics, toxicity, as well as mechanisms for promising candidate compound(s) in the full-length huntingtin knock-in mouse model. We will investigate the structure-activity relationship of newly synthesized analogs of 7,8-dihydroxyflavone in HD cell models. The promising candidate compound(s) will be further evaluated for therapeutic efficacy, pharmacokinetics, pharmacodynamics, and toxicity, as well as molecular mechanisms in the full-length huntingtin knock-in mouse model. The ultimate goal of the proposed research is to validate structural MRI and MRS as biomarkers for efficacy trials and prepare therapeutic candidate compounds for HD clinical trials.

描述（由申请人提供）：亨廷顿氏病（HD）是由亨廷顿基因突变引起的毁灭性神经退行性疾病。没有治疗可以阻止或减慢疾病的进展。要开发这种治疗需要客观的疾病进展措施。神经影像措施提供了对疾病进展的无偏见。关键问题是这些措施是否真正反映了中棘神经元的减少或功能障碍 - 有选择地死亡的HD神经细胞，以及神经影像学指标是否与其他临床特征相关；更重要的是，这些措施是否敏感，可靠地对治疗做出反应。我们提出采用两种非侵入性纵向神经影像制定措施，反映了神经元的不同特征，体内结构磁共振成像（MRI）和磁共振光谱（MRS），以确定这些度量是否提供了这些敏感和忠实的治疗效率的敏感和忠实的改进 - 对这些不合理的效果 - 习惯相关的惯例 - 相关的习惯习惯是在实现的，并确定了习惯的习惯，并提供了这些措施的影响。全长亨廷顿敲击小鼠模型。在特定的目标1中，我们将验证结构MRI测量为生物标志物，并确定它们对全长亨廷汀敲击小鼠中神经保护治疗的反应。我们将确定有或没有治疗的HDHQ250小鼠中MRI测量与功能障碍之间的相关性。在特定目标2中，我们将研究与疾病进展并行的脑代谢物改变，并确定这些代谢物是否通过在全长亨廷顿敲击小鼠中使用磁共振光谱来对神经保护治疗做出反应。我们假设纹状体代谢产物的改变反映了早期神经元功能障碍和神经元电路的损害。我们将确定这些改变的代谢产物是否对神经保护疗法有反应，以及在全长的亨廷顿敲击小鼠中，脑代谢产物改变与突变体亨廷顿蛋白的功能后果之间有什么关系。在特定目标3中，我们将通过使用HD细胞模型来鉴定临床候选小分子TRKB激动剂，并进一步评估临床前疗效，药代动力学，药效学，毒性，毒性，以及在全长Huntingtin敲门小鼠模型中具有有希望的候选化合物的机制。我们将研究HD细胞模型中7,8-二羟基氟酮的新合成类似物的结构活性关系。有希望的候选化合物将进一步评估治疗功效，药代动力学，药效学和毒性，以及全长猎人敲击小鼠模型中的分子机制。拟议研究的最终目标是验证结构性MRI和MRS作为功效试验的生物标志物，并为HD临床试验准备治疗候选化合物。