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:
- 金额:$ 22.46万
- 依托单位:
- 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:
- 关键词:AcuteAddressAdverse effectsAnabolismAnimal ModelAntiparkinson AgentsAreaBacteriaBenserazideBlood - brain barrier anatomyBradykinesiaBrainCarbidopaChromosomesChronicClinicalCodon NucleotidesCommunitiesComplexComplicationCorpus striatum structureDOPA decarboxylaseDataDevelopmentDiseaseDopaDopamineDopamine ReceptorDoseDrug KineticsDyskinetic syndromeEngineered ProbioticsEngineeringEscherichia coliExhibitsGenerationsGenesGeneticGenetic EngineeringGoalsGoldHealthHumanImpaired cognitionIn SituIn VitroInbred C57BL MiceIowaL-DOPA induced dyskinesiaLeadLegal patentLesionLevodopaMeasuresMixed Function OxygenasesModalityModelingModern MedicineMotorMusNatureNerve DegenerationNeuronsNeurotoxinsOralOral AdministrationOxidoreductaseParkinson DiseasePathway interactionsPatientsPerformancePharmaceutical PreparationsPharmacologic SubstancePhasePlasmaPlasmidsProbioticsProductionQuality of lifeReplacement TherapyRhamnoseRibosomal RNARodent ModelRotationSystemTabletsTherapeuticTimeTransgenic OrganismsTreatment EfficacyTremorUniversitiesWorkbasebehavioral phenotypingdecarboxylase inhibitordisease phenotypegut colonizationgut microbiomehost microbiotaimprovedin vivometagenomic sequencingmicrobialmicrobiomemitopark mousemotor deficitmotor impairmentmotor symptommouse modelneurochemistrynigrostriatal pathwaynovelnovel strategiesnovel therapeuticspharmacokinetics and pharmacodynamicsposture instabilitypre-clinicalpreclinical efficacypreventprobiotic supplementationprobiotic therapypromoterreduce symptomsresponseside effectstandard carestemsuccesstherapeutic developmenttranslational 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
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Anumantha Gounder Kanthasamy其他文献
Anumantha Gounder Kanthasamy的其他文献
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{{ truncateString('Anumantha Gounder Kanthasamy', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 22.46万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 22.46万 - 项目类别:
Novel Re-engineered L DOPA Probiotic Therapy for Parkinson's Disease
新型重新设计的左旋多巴益生菌疗法治疗帕金森病
- 批准号:
10688149 - 财政年份:2021
- 资助金额:
$ 22.46万 - 项目类别:
Protein Aggregation and Inflammasome Signaling in Manganese Neurotoxicity.
锰神经毒性中的蛋白质聚集和炎症小体信号传导。
- 批准号:
10508354 - 财政年份:2021
- 资助金额:
$ 22.46万 - 项目类别:
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
- 批准号:
10453379 - 财政年份:2021
- 资助金额:
$ 22.46万 - 项目类别:
Novel Re-engineered L DOPA Probiotic Therapy for Parkinson's Disease
新型重新设计的左旋多巴益生菌疗法治疗帕金森病
- 批准号:
10618744 - 财政年份:2021
- 资助金额:
$ 22.46万 - 项目类别:
Neuroinflammation and microglial Kv1.3 in Parkinsons disease
帕金森病中的神经炎症和小胶质细胞 Kv1.3
- 批准号:
10528896 - 财政年份:2017
- 资助金额:
$ 22.46万 - 项目类别:
Novel Mechanisms of Pesticide-Induced Neurotoxicity
农药引起的神经毒性的新机制
- 批准号:
9906057 - 财政年份:2017
- 资助金额:
$ 22.46万 - 项目类别:
Neuroinflammation and microglial Kv1.3 in Parkinsons disease
帕金森病中的神经炎症和小胶质细胞 Kv1.3
- 批准号:
9921502 - 财政年份:2017
- 资助金额:
$ 22.46万 - 项目类别:
Protein Aggregation and Inflammasome Signaling in Manganese Neurotoxicity
锰神经毒性中的蛋白质聚集和炎症小体信号转导
- 批准号:
9275981 - 财政年份:2016
- 资助金额:
$ 22.46万 - 项目类别:
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