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

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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.