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

亚甲蓝治疗亨廷顿病的体内纵向评估

基本信息

项目摘要

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.
描述(由申请人提供):亨廷顿病(HD)是一种毁灭性的遗传性神经退行性疾病,在生命的黄金时期发作,没有可用的疾病改善治疗。因此,鉴定可延迟疾病发作或减缓疾病进展的生物可利用和脑渗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),商业上称为“Rember”,是一种成功完成治疗阿尔茨海默病(AD)的IIb期临床试验的药物,在六个月后显示出认知功能的显著改善,并在一年内将AD的进展减缓了81%。MB具有在中枢神经系统中起作用的药物候选物所需的几种期望的性质,包括在水性介质中的高溶解度、穿过血脑屏障的能力、在CNS中起作用的能力和低溶解度。 在啮齿动物模型和人类中的毒性。因为它是在人类使用和多个FDA临床试验的神经系统疾病,它也代表了一个候选人,可以迅速转移到临床。我们测试了MB是否可以调节扩展的聚谷氨酰胺重复聚集中间体的形成并提供体内治疗益处。我们的初步数据表明,MB可能是一个有效的调制器的突变体Htt聚集过程中,是神经保护的细胞为基础的和果蝇模型,增加生产的BDNF和减缓运动障碍的时间过程中HD建模的R6/2小鼠。为了确定MB是否适用于人体临床试验,需要在一项长期临床前试验中对MB进行系统评估,其中包括多项结局指标,并检测症状前和症状给药时间。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。拟议的纵向研究将为理解聚集物种的时间进展和与疾病的关系以及MB在HD中的未来治疗应用奠定基础。提出了以下具体目的:目的:亚甲蓝处理的功效和BACHD转基因小鼠中聚集的调节。我们的目的是评估MB治疗在全长小鼠模型BACHD中的长期获益,确定MB的生物利用度,并研究聚集中间体、分子特征和神经病理学之间的时间关系。由于数据表明MB给药时间可能至关重要,因此治疗将在症状前阶段或疾病明显时开始开始。我们的方法将利用一系列试验,包括运动功能、行为、聚集中间体试验、脑病理学和基因表达分析来阐明MB效应。

项目成果

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Leslie Michels Thompson其他文献

Transcription meets metabolism in neurodegeneration
转录在神经退行性变中与代谢相遇
  • DOI:
    10.1038/nm1106-1239
  • 发表时间:
    2006-11-01
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Christopher A Ross;Leslie Michels Thompson
  • 通讯作者:
    Leslie Michels Thompson

Leslie Michels Thompson的其他文献

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{{ truncateString('Leslie Michels Thompson', 18)}}的其他基金

Molecular Mechanisms of Pathogenesis in Huntington’s disease
亨廷顿病发病机制的分子机制
  • 批准号:
    10452484
  • 财政年份:
    2020
  • 资助金额:
    $ 7.73万
  • 项目类别:
Molecular Mechanisms of Pathogenesis in Huntington’s disease
亨廷顿病发病机制的分子机制
  • 批准号:
    10619620
  • 财政年份:
    2020
  • 资助金额:
    $ 7.73万
  • 项目类别:
Molecular Mechanisms of Pathogenesis in Huntington’s disease
亨廷顿病发病机制的分子机制
  • 批准号:
    10652688
  • 财政年份:
    2020
  • 资助金额:
    $ 7.73万
  • 项目类别:
From Structure to Therapy: The TRiC Chaperonin Network in Huntington's Disease
从结构到治疗:亨廷顿病中的 TRiC 伴侣蛋白网络
  • 批准号:
    9074429
  • 财政年份:
    2016
  • 资助金额:
    $ 7.73万
  • 项目类别:
From Structure to Therapy: The TRiC Chaperonin Network in Huntington's Disease
从结构到治疗:亨廷顿病中的 TRiC 伴侣蛋白网络
  • 批准号:
    9249123
  • 财政年份:
    2016
  • 资助金额:
    $ 7.73万
  • 项目类别:
Genome editing in HD iPS cells to reduce mutant and total Huntington expression
HD iPS 细胞中的基因组编辑可减少突变体和总亨廷顿表达
  • 批准号:
    8970040
  • 财政年份:
    2015
  • 资助金额:
    $ 7.73万
  • 项目类别:
Genome editing in HD iPS cells to reduce mutant and total Huntington expression
HD iPS 细胞中的基因组编辑可减少突变体和总亨廷顿表达
  • 批准号:
    9109084
  • 财政年份:
    2015
  • 资助金额:
    $ 7.73万
  • 项目类别:
In vivo longitudinal assessment of methylene blue for Huntington's disease
亚甲蓝治疗亨廷顿病的体内纵向评估
  • 批准号:
    8583167
  • 财政年份:
    2014
  • 资助金额:
    $ 7.73万
  • 项目类别:
Neuroregulatory Mechanisms of PIAS1 and Implications for Huntington's Disease
PIAS1 的神经调节机制及其对亨廷顿病的影响
  • 批准号:
    8921782
  • 财政年份:
    2014
  • 资助金额:
    $ 7.73万
  • 项目类别:
Training Program in Stem Cell Translational Medicine for Neurological Disorders
神经系统疾病干细胞转化医学培训项目
  • 批准号:
    8869057
  • 财政年份:
    2013
  • 资助金额:
    $ 7.73万
  • 项目类别:
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