Evaluation of In Vivo Efficacy of a Novel Microbial Therapy to Treat Cognitive Deficits in Alzheimers disease

项目总结/摘要 阿尔茨海默病（AD）是痴呆的主要原因，但没有有效的治疗干预 对于那些在前驱期和早期阶段的AD。早期疾病中功能和认知恢复力的恢复 阶段在许多方面特别有益，因为它可以大大延长生活质量的时间， 延缓AD的临床发作。为了寻找早期疾病阶段的治疗靶点，最近的研究发现， MCI和AD早期患者的蓝斑（LC）TH+神经元显著丢失。这些 神经元投射到海马体，在那里单胺神经递质，如多巴胺（DA）和 去甲肾上腺素（NE）调节突触可塑性和与记忆和认知相关的神经元功能。 因此，海马中DA和NE水平的恢复可以在早期阶段保持认知弹性 的AD。左旋多巴是多巴胺的脑渗透前体药物，用于治疗帕金森病。它的治疗功效 在人类中对AD的研究还没有很好，部分原因是缺乏对AD病理机制的了解。 DA和NE参与AD和神经行为副作用的发展， 使用.因此，我们建议通过一种新的方法来综合评价左旋多巴的治疗效果 在小鼠模型中的施用重现了AD表型的早期阶段。不同于传统的口头 每天多次施用L-DOPA，这导致血浆中L-DOPA的波动并诱导 毒性，我们将给予工程菌，生产左旋多巴（EcNrhaL-DOPA）在一个持续的和非- 搏动的方式。单次施用EcNrhaL-DOPA在肠道中短暂停留几天， 供应左旋多巴而不破坏肠道微生物群。这种方法可以有效地减少波动- 介导的副作用和L-DOPA毒性，并最大限度地发挥其治疗作用，以恢复脑DA和NE 程度.作为在相关AD小鼠模型中评估其治疗益处的第一步，我们建议 为了优化在APP-KI和野生型小鼠中给予EcNrhaL-DOPA的治疗方案和剂量， 评价本申请中的药代动力学和任何不良毒理学效应。总体影响和 这项研究的翻译意义是非常高的，因为这种方法不仅可以工作 与目前可用的治疗AD的药物互补，而且还显著减缓AD的进展 从早期阶段的表型，以防止转化为AD的全谱。这项新技术涵盖了 在USPTO申请号20190262298下，标题为“L-DOPA微生物组疗法”。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a leading cause of dementia, yet no effective therapeutic intervention is available for those in prodromal and early stages of AD. Restoration of functional and cognitive resilience in early disease stages is especially beneficial in many aspects as it could substantially extend the period of quality of life and delay the clinical onset of AD. In search of therapeutic targets for early disease stages, recent studies uncover a significant loss of TH+ neurons in locus coeruleus (LC) in patients with MCI and very early stages of AD. These neurons project to the hippocampus, where monoamine neurotransmitters, such as dopamine (DA) and norepinephrine (NE), modulate synaptic plasticity and neuronal functions relevant to memory and cognition. Thus, restoration of DA and NE levels in the hippocampus could retain cognitive resilience during early stages of AD. L-DOPA is a brain penetrating precursor drug for DA to treat Parkinson’s disease. Its therapeutic potency on AD has not been well investigated in humans in part due to lack of understanding in the pathological involvement of DA and NE in AD and development of neurobehavioral side-effects for frequent and long-term use. We, therefore, propose to comprehensively evaluate the therapeutic efficacy of L-DOPA by a novel method of administration in the mouse model recapitulating early stage of AD phenotypes. Unlike the traditional oral administration of L-DOPA multiple times a day, which results in fluctuation of L-DOPA in plasma and induces toxicity, we will give engineered commensal bacteria that produce L-DOPA (EcNrhaL-DOPA) in a sustained and non- pulsatile manner. Single administration of EcNrhaL-DOPA transiently resides in the gut for a couple of days and supply L-DOPA without disrupting the gut microbiota. This approach could effectively mitigate fluctuation- mediated side-effects and L-DOPA toxicity and maximize its therapeutic effects to restore brain DA and NE levels. As a first step towards evaluating its therapeutic benefits in the relevant AD mouse model, we propose to optimize the treatment regimen and dosage of EcNrhaL-DOPA administration in APP-KI and wildtype mice and to evaluate pharmacokinetics and any adverse toxicological effects in this application. The overall impact and translational significance of this proposed study are extremely high as this approach could not only work complementally with currently available drugs to treat AD but also significantly slow the progression of AD phenotypes from early stages to prevent conversion to full spectrum of AD. This novel technology is covered under USPTO Application # 20190262298, titled “L-DOPA microbiome therapy”.