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Novel Re-engineered L DOPA probiotic therapy for Parkinsons Disease

新型重新设计的左旋多巴益生菌疗法治疗帕金森病

基本信息

批准号：
10043372
负责人：
Anumantha Gounder Kanthasamy
金额：
$ 22.46万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-07-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10043372
关键词：
Acute Address Adverse effects Anabolism Animal Model Antiparkinson Agents Area Bacteria Benserazide Blood - brain barrier anatomy Bradykinesia Brain Carbidopa Chromosomes Chronic Clinical Codon Nucleotides Communities Complex Complication Corpus striatum structure DOPA decarboxylase Data Development Disease Dopa Dopamine Dopamine Receptor Dose Drug Kinetics Dyskinetic syndrome Engineered Probiotics Engineering Escherichia coli Exhibits Generations Genes Genetic Genetic Engineering Goals Gold Health Human Impaired cognition In Situ In Vitro Inbred C57BL Mice Iowa L-DOPA induced dyskinesia Lead Legal patent Lesion Levodopa Measures Mixed Function Oxygenases Modality Modeling Modern Medicine Motor Mus Nature Nerve Degeneration Neurons Neurotoxins Oral Oral Administration Oxidoreductase Parkinson Disease Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacologic Substance Phase Plasma Plasmids Probiotics Production Quality of life Replacement Therapy Rhamnose Ribosomal RNA Rodent Model Rotation System Tablets Therapeutic Time Transgenic Organisms Treatment Efficacy Tremor Universities Work base behavioral phenotyping decarboxylase inhibitor disease phenotype gut colonization gut microbiome host microbiota improved in vivo metagenomic sequencing microbial microbiome mitopark mouse motor deficit motor impairment motor symptom mouse model neurochemistry nigrostriatal pathway novel novel strategies novel therapeutics pharmacokinetics and pharmacodynamics posture instability pre-clinical preclinical efficacy prevent probiotic supplementation probiotic therapy promoter reduce symptoms response side effect standard care stem success therapeutic development translational approach

项目摘要

Abstract The complex and prolonged disease course exhibited by Parkinson’s disease (PD) first starts with non- motor disturbances and then slowly progresses to mild-to-moderate motor deficits, ultimately inflicting severe movement impairment and cognitive decline. Dopamine deficiency resulting from nigrostriatal dopaminergic neuronal damage ultimately manifests as the cardinal extrapyramidal motor symptoms of rigidity, bradykinesia, tremors, and postural instability. This proposal addresses one of the greatest challenges facing the current anti- Parkinsonian therapy of dopamine replacement with the dopamine precursor L-DOPA. Currently, oral tablet dosing of L-DOPA/carbidopa 3-4 times/day remains the most effective and well-tolerated treatment, one that significantly improves the motor symptoms and quality of life of patients in the early stages of PD. However, due to its non-continuous, pulsatile delivery of L-DOPA to the brain, long-term L-DOPA administration causes deleterious side effects, including L-DOPA-induced dyskinesia (LID) among other motor complications, in the majority of patients. To achieve sustained symptomatic relief without severe L-DOPA-associated motor complications, including dyskinesia, we propose that systemic delivery of genetically engineered, chromosome- integrated, and regulatable L-DOPA-producing probiotic bacteria will avoid fluctuations in plasma L-DOPA levels and provide a more consistent delivery of L-DOPA to the brain where it can be converted to a continuous supply of dopamine in the nigrostriatal pathway. Thus, we aim to systematically evaluate the treatment feasibility and efficacy of this novel microbiome-based platform for the continuous delivery of L-DOPA in relieving motor symptoms without inducing severe dyskinesia. The scientific premise of the work is supported by key preliminary data demonstrating that: 1) the genetically reengineered, chromosome-integrated, and regulatable L-DOPA-producing E. coli Nissle 1917 probiotic strain (EcNrhaL-DOPA) efficiently produce L-DOPA both in vitro and in vivo than the older plasmid-based system, and 2) oral administration 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 PD patients, and increases L-DOPA and dopamine levels in the brain. To further expand our novel preliminary results, we will pursue the following specific aims: R61 phase (i) determine the dose-response effect of orally administered EcNrhaL-DOPA on gut colonization as well as its pharmacokinetic and adaptation profiles in both C57BL and MitoPark mice; R33 phase (ii) determine the therapeutic efficacy of EcNrhaL-DOPA in the MitoPark and 6-OHDA-lesioned mouse models of PD, and (iii) determine whether sustained delivery of microbial L-DOPA prevents LID in two mouse models of LID. Our novel therapeutic pipeline strategy involving chronic delivery of probiotic L-DOPA is expected to transform the dopaminergic therapeutic modalities for PD.

摘要