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: 10527152
• 负责人: Anumantha Gounder Kanthasamy
• 金额: $ 145.92万
• 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/10527152
• 关键词: Ablation; Address; Adverse effects; Affect; Agitation; Alzheimer' s Disease; 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; Gold; Human; Impaired cognition; In Vitro; Inflammation; L-DOPA induced dyskinesia; Lead; Legal patent; Levodopa; 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; Time; Toxicology; Transgenic Organisms; Treatment Efficacy; Ventral Tegmental Area; base; canine model; cholinergic; dopamine replacement therapy; drug development; effective therapy; 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; therapeutic evaluation; 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基因工程细菌生物学来治疗 阿尔茨海默病 (AD) 最常见的早期症状，包括认知障碍和其他 神经心理症状，例如焦虑和抑郁，这种使人衰弱的疾病造成了巨大的影响。 没有有效的缓解 AD 疾病的药物可以减轻社会的情感、社会和经济负担。 目前 FDA 批准的胆碱能和 tau 蛋白病与疾病进展相关。 谷氨酸神经治疗药物在挽救轻度认知障碍 (MCI) 患者的记忆方面充其量是非常有限的 以及 AD 病例的前驱期或早期阶段，通常会加重焦虑、冷漠、抑郁、激越和其他症状 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 是一种疾病。 认知和行为症状的发生和进展涉及神经回路缺陷。 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 DA/NE 输入具有成为缓解​​症状的有效方法的巨大潜力 AD 患者的认知和行为缺陷，甚至可以延迟疾病的发作。目前，L-口服片剂给药。 DOPA/卡比多巴 3-4 次/天仍然是恢复人类大脑 DA/NE 水平的最有效疗法。 然而，这种重复的慢性脉冲输送会导致严重的副作用，因此，我们的治疗假设。 为了解决这一未满足的临床问题，系统性地递送基因工程左旋多巴细菌活体 治疗（LDBL）将避免血浆左旋多巴的大幅波动，并提供更一致的左旋多巴输送 DOPA 进入大脑，将 DA/NE 恢复到稳定水平，从而更好地缓解 AD 症状，无需额外的副作用 我们的概念验证数据支持：1) 基因工程益生菌大肠杆菌 Nissle 1917 菌株。 (EcNL-DOPA) 在体外和体内均能有效产生 L-DOPA，2) 口服给药的 EcNL-DOPA 很容易在体内定殖 小鼠肠道，达到与临床有效血浆相对应的稳态血浆 L-DOPA 水平 人类的水平，并增加啮齿动物和犬科动物大脑中的 L-DOPA 和 DA/NE 水平，以及 3) EcNL-DOPA 治疗可改善 AD 动物模型的神经行为结果并降低 Aβ 水平，包括 我们正在申请专利的 ADDP 策略的总体目标是优化领先的 LDBL 并进行测试。 其在缓解早期 AD 的认知和行为缺陷（例如冷漠）方面的临床前功效。 为了实现这一目标，我们将追求以下具体目标：(i) 优化用于动物测试的先导 LDBL，(ii) 评估主要 LDBL 的慢性药代动力学 (PK) 和安全性，以进行临床前疗效研究， (iii) 确定两种先导 LDBL 在转基因 (Tg) AD 啮齿动物模型中的体内药效 (PD) 功效， (iv) 评估我们独特的痴呆犬模型中最有效的先导 LDBL 的功效。 涉及长期输送益生菌 L-DOPA 的治疗管道策略预计将建立一条新的生产线 基于工程微生物组的单胺神经治疗方法治疗 AD 相关痴呆症 (ADRD)。