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

描述(申请人提供)：亨廷顿病(HD)是一种毁灭性的遗传性神经退行性疾病，发作在壮年，没有可用的疾病修改治疗。因此，确定可以延缓疾病发病或延缓疾病进展的生物可用和脑穿透药物是开发有效的HD治疗干预措施的关键组成部分。亚甲蓝(MB)是一种成功地完成了治疗阿尔茨海默病(AD)的IIb期临床试验的药物，在6个月后显示出认知功能的显著改善，并在一年的过程中减缓了AD的进展81%。亚甲蓝(MB)在中枢神经系统作用的候选药物具有几个理想的特性，包括在水介质中的高溶解度，穿越血脑屏障的能力，在中枢神经系统的作用能力，以及低水平的 对啮齿动物模型和人类的毒性。因为它在人类使用，并在FDA的多个神经疾病临床试验中使用，它也代表了一种可以迅速转移到临床的候选药物。我们在体内测试MB是否可以调节扩大的聚谷氨酰胺重复聚集中间产物的形成并提供治疗益处。我们的初步数据表明，MB可能是突变的Htt聚集过程的有效调节器，在基于细胞的模型和果蝇模型中具有神经保护作用，增加BDNF的产生，并减缓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于人类临床试验，需要在长期的临床前试验中对甲基溴进行系统的评估，包括多项结果测量和症状前和症状给药时间的测试。在这里，我们建议使用全长BAC HD小鼠模型来研究MB对行为、神经病理学、分子特征和生物利用度的潜在疾病改善作用。这项拟议的纵向研究将为了解聚集物种的时间进程及其与疾病的关系，以及未来MB在HD治疗中的应用奠定基础。目的：亚甲蓝对BACHD转基因小鼠的治疗作用及对聚集的调节作用。我们的目的是评估MB治疗全长小鼠模型BACHD的长期益处，确定MB的生物利用度，并调查聚集中间体、分子特征和神经病理学之间的时间关系。由于数据表明，甲基溴给药的时机可能很关键，治疗将在症状前阶段或疾病明显时开始。我们的方法将利用包括运动功能、行为、聚集中间体分析、脑病理和基因表达分析在内的一系列分析来阐明MB的作用。

DESCRIPTION (provided by applicant): 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.