Huntington's disease biomarkers and therapeutics

描述(申请人提供)：亨廷顿病(HD)是一种由亨廷顿蛋白基因突变引起的毁灭性的神经退行性疾病。没有任何治疗方法可以预防或延缓疾病的发展。要开发这样的治疗方法，需要客观地衡量疾病的进展情况。神经成像措施提供了对疾病进展的无偏见检测。关键问题是，这些措施是否真的反映了中等棘神经元的减少或功能障碍--HD中选择性死亡的神经细胞，以及神经成像措施是否与其他临床特征相关；更重要的是，这些措施是否对治疗做出了敏感和可靠的反应。我们建议使用两种反映神经元不同特征的非侵入性纵向神经成像指标，即活体结构磁共振成像(MRI)和磁共振波谱(MRS)，以确定这些指标是否能够灵敏和真实地反映治疗效果，以及这些非侵入性指标与亨廷顿蛋白基因敲入突变小鼠模型中亨廷顿蛋白引起的功能损害之间的关系。在具体目标1中，我们将验证结构磁共振测量作为生物标记物，并确定它们对全长亨廷顿基因敲入小鼠神经保护治疗的反应。我们将确定HdhQ250小鼠在接受或不接受治疗的情况下，MRI测量与功能损害之间的相关性。在特定的目标2中，我们将在疾病进展的同时研究大脑代谢物的变化，并通过使用核磁共振波谱来确定这些代谢物对全长亨廷顿基因敲入小鼠的神经保护治疗是否有反应。我们假设纹状体代谢物的改变反映了早期神经元功能障碍和神经元回路受损。我们将确定这些改变的代谢物是否对神经保护治疗有反应，以及在全长Huntingtin敲入小鼠中，大脑代谢物改变与突变Huntingtin的功能后果之间有什么关系。在具体目标3中，我们将利用HD细胞模型寻找临床候选小分子TrkB激动剂(S)，并进一步评估其在亨廷顿蛋白基因敲入小鼠模型中的临床前疗效、药代动力学、药效学、毒性以及潜在候选化合物(S)的机制。我们将在HD细胞模型中研究新合成的7，8-二羟基黄酮类似物的构效关系。有希望的候选化合物(S)将在亨廷顿蛋白基因敲入小鼠全长模型中进一步评估治疗效果、药代动力学、药效学和毒性以及分子机制。这项拟议研究的最终目标是验证结构MRI和MRS作为疗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。

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.