In vivo longitudinal assessment of methylene blue for Huntington's disease

项目摘要/摘要： 亨廷顿病(HD)是一种发生在壮年时期的破坏性遗传性神经退行性疾病 没有可用的疾病修正治疗。生物利用型和脑透性药物的鉴定 因此，可以延缓或延缓疾病进展的药物是开发有效药物的关键组成部分 HD的治疗性干预。亚甲蓝(MB)，商业上称为“Member”，是一种 成功完成治疗阿尔茨海默病(AD)的IIb期临床试验，显示出 6个月后认知功能显著改善，AD进展速度比 为期一年的课程。甲基溴有几个所需的性能要求的药物候选作用于中央 神经系统，包括在水介质中的高溶解度，跨越血脑屏障的能力， 在中枢神经系统中发挥作用的能力，在啮齿动物模型和人类中的毒性低。因为它是人类使用的，而且在 FDA针对神经疾病的多项临床试验，它也代表了一种可以迅速移动的候选者 去诊所。我们测试了MB是否可以调节扩展的聚谷氨酰胺重复聚集的形成 中间体，并在体内提供治疗益处。我们的初步数据表明，甲基溴可能是 突变型Htt聚集过程的有效调节剂在细胞和果蝇中具有神经保护作用 增加脑源性神经营养因子的产生，并延缓HD模型R6/2小鼠运动障碍的时间进程。 为了确定甲基溴是否适合进行人体临床试验，对甲基溴进行了长期的系统评估 临床前试验，采用多种结果测量并测试症状前和症状出现时间 管理是必需的。在这里，我们建议使用全长BAC HD小鼠模型来研究潜在的 亚甲基溴对行为、神经病理、分子特征和生物利用度的疾病改善作用。这个 拟议的纵向研究将为理解 聚集体的种类和与疾病的关系，以及MB在HD治疗中的未来应用。以下是 目的：亚甲基蓝的治疗效果及对血管内皮细胞聚集的调节 BACHD转基因小鼠。我们的目标是全面评估甲基溴治疗的长期益处。 建立小鼠BACHD模型，测定MB的生物利用度，并研究两者之间的时间关系 聚集中间体、分子特征和神经病理学。由于数据表明， 甲基溴给药可能很关键，治疗将在症状前阶段或在疾病发生时开始 这是显而易见的。我们的方法将利用一组分析，包括运动功能，行为，分析 聚集中间体，脑病理和基因表达分析，以阐明MB的作用。

Project Summary/Abstract: Huntington's disease (HD) is a devastating inherited neurodegenerative disease that strikes in the prime of life with no available disease modifying treatment. The identification of bioavailable and brain penetrable drugs that can delay onset or slow progression of disease is therefore a crucial component to developing effective therapeutic interventions for HD. Methylene blue (MB), known commercially as rember", is a drug that successfully completed a Phase IIb clinical trial for the treatment of Alzheimer's disease (AD), showing a significant improvement in cognitive function after six months and slowing the progression of AD by 81% over the course of one year. MB has several desirable properties required for drug candidates that act in the central nervous system, including high solubility in aqueous media, the ability to cross the blood-brain barrier, the ability to act in the CNS, and low toxicity in rodent models and in humans. Because it is in human use and in multiple FDA clinical trials for neurological disorders, it also represents a candidate that can be rapidly moved to the clinic. We tested if MB could modulate formation of expanded polyglutamine repeat aggregation intermediates and provide therapeutic benefit in vivo. Our preliminary data demonstrates that MB may be a potent modulator of the mutant Htt aggregation process, is neuroprotective in cell-based and Drosophila models, increases production of BDNF and slows the time course of motor deficits in HD modeled R6/2 mice. To determine if MB may be appropriate for human clinical trials, a systematic assessment of MB in a long-term pre-clinical trial with multiple outcome measures and testing presymptomatic and symptomatic time of administration is required. Here we propose to use a full length BAC HD mouse model to investigate potential disease modifying effects of MB on behavior, neuropathology, molecular signatures and bioavailability. The proposed longitudinal study will lay the fundamental groundwork for understanding the temporal progression of aggregation species and relationship to disease, and future therapeutic application of MB for HD. The following specific aim is proposed: Aim: Efficacy of Methylene Blue treatment and modulation of aggregation in BACHD transgenic mice. Our aim is to evaluate the long-term benefit of MB treatment in the full length mouse model BACHD, determine bioavailability of MB and investigate the temporal relationship between aggregation intermediates, molecular signatures and neuropathology. Since data suggests that the timing of MB administration may be critical, treatment will begin during either a presymptomatic stage or when disease is evident. Our approach will utilize a battery of assays including motor function, behavior, assays of aggregation intermediates, brain pathology and gene expression analysis to elucidate MB effects.