Novel Reengineered Microbiome-based Biologic Therapy to Treat Cognitive and Behavioral Symptoms of Alzheimer's Disease and Related Dementias

基于微生物组的新型生物疗法可治疗阿尔茨海默病和相关痴呆症的认知和行为症状

• 批准号: 10677787
• 负责人: Anumantha Gounder Kanthasamy
• 金额: $ 150.35万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677787
• 关键词: Ablation; Address; Adverse effects; Affect; Agitation; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Disease Models; Animal Model; Animal Testing; Anxiety; Bacteria; Behavioral; Behavioral Symptoms; Biological; Biological Assay; Biological Response Modifier Therapy; Biomedical Engineering; Brain; Canis familiaris; Carbidopa; Cerebrum; Chromosomes; Chronic; Clinical; Cognitive; Data; Dementia; Disease; Disease Progression; Dopamine; Dopamine Agonists; Dopamine Uptake Inhibitors; Dose; Drug Kinetics; Emotional; Engineered Probiotics; Engineering; Escherichia coli; Evaluation; Executive Dysfunction; FDA approved; Financial Hardship; Flavin-Adenine Dinucleotide; Frequencies; Genes; Genetic Engineering; Glutamates; Goals; Human; Impaired cognition; In Vitro; Inflammation; L-DOPA induced dyskinesia; Lead; Legal patent; Link; Medical; Memory; Mental Depression; Microbial Genetics; Mixed Function Oxygenases; Modality; Motivation; Mus; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropsychology; Neurotransmitters; Norepinephrine; Onset of illness; Oral; Oral Administration; Outcome; Oxidoreductase; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Play; Probiotics; Production; Property; Regulatory Element; Rhamnose; Ritalin; Rodent; Rodent Model; Role; Safety; Senile Plaques; Signal Transduction; Societies; Standardization; Symptoms; Synapses; System; Tablets; Testing; Therapeutic; Toxicology; Transgenic Organisms; Treatment Efficacy; Ventral Tegmental Area; canine model; cholinergic; dopamine replacement therapy; drug development; effective therapy; efficacy evaluation; efficacy study; gastrointestinal; gut colonization; gut health; gut microbiome; improved; in vitro testing; in vivo; in vivo Model; ineffective therapies; irritation; lead optimization; locus ceruleus structure; microbiome; mild cognitive impairment; monoamine; mortality; mouse model; neural circuit; neurobehavioral; neurochemistry; neuroinflammation; neuron loss; neurotransmission; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; preclinical efficacy; programs; promoter; reduce symptoms; resilience; side effect; small molecule; social; standard care; sugar; symptom treatment; targeted treatment; tau Proteins; tau-1; therapeutic biomarker; translational approach

Abstract Our early-stage ADDP proposal aims to develop a novel genetically engineered bacterial biologic to treat the most common early symptoms of Alzheimer's disease (AD), including cognitive impairment and other neuropsychological symptoms, such as anxiety and depression. This debilitating disease imposes a huge emotional, social and financial burden on society. No effective disease-modifying AD drug exists to dampen the Aβ and tau proteinopathies associated with disease progression. Current FDA-approved cholinergic and glutamatergic neurotherapeutics are very modest at best in rescuing memory in mild cognitive impairment (MCI) and prodromal or early stages of AD cases, and often worsen anxiety, apathy, depression, agitation, and other neurobehavioral symptoms, GI irritations, and even mortality. Recent biological evidence indicates that AD is a neural circuit disorder. The onset and progression of cognitive and behavioral symptoms involve a deficiency in monoamine neurotransmitter signaling networks, including norepinephrine (NE) and dopamine (DA). Thus, we propose that restoring brain DA/NE inputs holds the excellent potential to be an effective approach to alleviating cognitive and behavioral deficits in AD and could even delay disease onset. Currently, oral tablet dosing of L- DOPA/carbidopa 3-4 times/day remains the most effective therapy at restoring brain DA/NE levels in humans. However, this repeated chronic pulsatile delivery causes severe side effects. Thus, our therapeutic hypothesis to address this unmet clinical problem is that systemic delivery of genetically engineered L-DOPA bacterial live- therapeutics (LDBL) will avoid large fluctuations in plasma L-DOPA and provide more consistent delivery of L- DOPA to the brain for restoring DA/NE to stable levels that better relieve AD symptoms without additional side effects. Our proof-of-concept data support that 1) the genetically engineered probiotic E. coli Nissle 1917 strains (EcNL-DOPA) efficiently produce L-DOPA both in vitro and in vivo, 2) oral dosing of EcNL-DOPA readily colonizes the mouse gut, achieves a steady-state plasma L-DOPA level that corresponds to the clinically effective plasma level in humans, and increases L-DOPA and DA/NE levels in the brain of rodents and canines, and 3) EcNL-DOPA treatment leads to improved neurobehavioral outcomes and reduces Aβ levels in AD animal models including canines. The overarching goal of our patent-pending ADDP strategy is to optimize the lead LDBL and test its preclinical efficacy in alleviating the cognitive and behavioral deficits, such as apathy, of early AD. To achieve this goal, we will pursue the following specific aims: (i) Optimize the lead LDBL for animal testing, (ii) Evaluate the chronic pharmacokinetic (PK), and safety profile of the lead LDBLs for preclinical efficacy studies, (iii) Determine in vivo pharmacodynamic (PD) efficacy of two lead LDBLs in transgenic (Tg) AD rodent models, and (iv) Assess the efficacy of the most effective lead LDBL in canine models of dementia. Together, our unique therapeutic pipeline strategy involving chronic delivery of probiotic L-DOPA is expected to establish a new line of engineered microbiome-based monoamine neurotherapeutic modalities for AD-related dementias (ADRD).

抽象的 我们的早期ADDP提案旨在开发一种新型的基因工程细菌生物学，以治疗 阿尔茨海默氏病（AD）最常见的早期症状，包括认知障碍和其他 神经心理学症状，例如焦虑和抑郁。这种使人衰弱的疾病不可能巨大 情感，社会和经济烧伤对社会。不存在有效调整疾病的AD药物来该死 与疾病进展相关的Aβ和TAU蛋白质病。当前FDA批准的胆碱能和 谷氨酸能神经疗法在挽救轻度认知障碍（MCI）的记忆中非常适中（MCI） AD病例的前驱或早期阶段，并且经常担心焦虑，冷漠，抑郁，躁动和其他 神经行为症状，胃肠道刺激甚至死亡率。最近的生物学证据表明AD是 神经回路障碍。认知和行为症状的发作和进展涉及 单胺神经递质信号网络，包括去甲肾上腺素（NE）和多巴胺（DA）。 提出恢复大脑/NE输入的提议具有减轻有效方法的极大潜力 认知和行为在AD中定义，甚至可能延迟疾病发作。目前，口服片剂l- DOPA/Carbidopa 3-4次/天仍然是恢复人类大脑DA/NE水平的最有效疗法。 但是，这种反复的慢性脉冲递送会导致严重的副作用。那，我们的治疗假设 解决这个未得到满足的临床问题的是，全身性地递送一般设计的L-DOPA细菌活性 治疗（LDBL）将避免在血浆L-DOPA中发生较大的波动，并提供更一致的L- DOPA到大脑，以将DA/NE恢复到稳定的水平，从而更好地挽救AD症状而没有其他方面 效果。我们的概念证明数据支持1）一般设计的益生菌大肠杆菌Nissle 1917菌株 （ECNL-DOPA）在体外和体内有效产生L-DOPA，2）ECNL-DOPA的口服剂量很容易殖民 小鼠肠道，达到与临床有效等离子体相对应的稳态等离子体L-DOPA水平 人类的水平，并增加啮齿动物和犬大脑中的L-DOPA和DA/NE水平，以及3）ECNL-DOPA 治疗可改善神经行为结局，并降低AD动物模型中的Aβ水平 犬。我们正在申请专利的ADDP策略的总体目标是优化铅LDBL并测试 它在缓解认知和行为的临床前效率定义了早期AD的冷漠。 为了实现这一目标，我们将追求以下特定目标：（i）优化用于动物测试的铅LDBL，（ii） 评估慢性药代动力学（PK）和铅LDBL的安全性，用于临床前效率研究， （iii）确定在转基因（TG）AD啮齿动物模型中两个铅LDBL的体内药效学（PD）效率， （iv）评估最有效的铅LDBL在痴呆犬模型中的效率。在一起，我们的独特之处 涉及益生菌L-DOPA的长期输送的治疗管道策略有望建立一条新系列 基于工程的微生物组的单胺神经治疗方式，用于广告相关痴呆症（ADRD）。