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).

摘要