Huntington's disease biomarkers and therapeutics

描述（由申请人提供）：亨廷顿氏病（HD）是一种由亨廷顿基因突变引起的毁灭性神经退行性疾病。没有任何治疗可以预防或减缓疾病进展。开发这种治疗方法需要对疾病进展进行客观测量。神经影像学措施提供疾病进展的公正检测。关键问题是这些测量是否真正反映了中棘神经元（HD患者选择性死亡的神经细胞）的减少或功能障碍，以及神经影像学测量是否与其他临床特征相关；更重要的是这些措施对治疗的反应是否敏感和可靠。我们建议采用两种反映神经元不同特征的非侵入性纵向神经成像方法，即体内结构磁共振成像（MRI）和磁共振波谱（MRS），来确定这些方法是否能敏感和忠实地反映治疗效果，以及这些非侵入性方法如何与全长亨廷顿敲入小鼠模型中突变亨廷顿诱导的功能损伤相关联。在Specific Aim 1中，我们将验证结构MRI测量作为生物标志物，并确定它们对全长亨廷顿蛋白敲入小鼠的神经保护治疗的反应。我们将确定MRI测量与HdhQ250小鼠接受或不接受治疗的功能损伤之间的相关性。在Specific Aim 2中，我们将研究与疾病进展平行的脑代谢物变化，并确定这些代谢物是否对全长亨廷顿蛋白敲入小鼠的神经保护治疗有反应。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的损伤。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，以及在全长亨廷顿敲入小鼠中，大脑代谢物改变与突变亨廷顿蛋白的功能后果之间的关系。在Specific Aim 3中，我们将通过HD细胞模型确定临床候选小分子TrkB激动剂，并在全长亨廷顿蛋白敲入小鼠模型中进一步评估临床前疗效、药代动力学、药效学、毒性以及有希望的候选化合物的机制。我们将研究新合成的7,8-二羟黄酮类似物在HD细胞模型中的构效关系。这些候选化合物将在全长亨廷顿蛋白敲入小鼠模型中进一步评估其治疗效果、药代动力学、药效学、毒性以及分子机制。该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临床试验制备治疗候选化合物。

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.