Pre-Clinical Evaluation of a Rationally Designed Nanotherapeutic for Huntington's Disease
合理设计的亨廷顿病纳米疗法的临床前评估
基本信息
- 批准号:10258489
- 负责人:
- 金额:$ 51.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseBacterial Artificial ChromosomesBiological AssayBrainBrain-Derived Neurotrophic FactorCAG repeatCalciumCell DeathClinical TrialsCodeCognitiveCommunicationCorpus striatum structureDevelopmentDiseaseDopamine D2 ReceptorElectrophysiology (science)FDA approvedFunctional disorderGenesGlutamatesGoalsGoldGuidelinesHand StrengthHealthHumanHuntington DiseaseHuntington geneHuntington proteinImageImpaired cognitionImpairmentIn VitroInheritedInjectionsInterruptionInvoluntary MovementsIschemic StrokeLinkLongevityMediatingMemantineMental disordersModelingMolecularMotorMusN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNMDA receptor antagonistNational Institute of Neurological Disorders and StrokeNerve DegenerationNeurodegenerative DisordersNeurologicNeuronsOutcomePathogenesisPathogenicityPatientsPharmacologyPharmacotherapyPhasePhysiologicalPilot ProjectsPlayPolymersPredispositionPreparationProductionPropertyRNARoleRouteSynapsesSynaptic CleftSystemTestingTherapeuticToxic effectTransgenic MiceTransgenic OrganismsTraumatic Brain InjuryTrinucleotide Repeat ExpansionValidationWorkanalytical methodbasecellular pathologycohortcytotoxicitydesigndisease phenotypedosageefficacious treatmentefficacy studyexcitotoxicityin vitro Assayin vivoin vivo Modelinsightmitochondrial dysfunctionnanoparticlenanotherapeuticneuron lossneuropathologyneuroprotectionneurotoxicitynovelpharmacokinetics and pharmacodynamicspolyglutaminepreclinical efficacypreclinical evaluationpreclinical trialpreservationpreventprotein expressionside effectstemsynaptic inhibitiontherapy development
项目摘要
PROJECT SUMMARY
Huntington’s disease (HD) is an inherited CAG-polyglutamine repeat expansion neurodegenerative disorder
characterized by cognitive and psychiatric impairment. HD is associated with synaptic dysfunction and neuronal
loss in the corticostriatal system of the brain. In HD, increased susceptibility of neurons to glutamatergic
excitotoxicity has been linked to activation of extrasynaptic NMDA receptors (eNMDARs) located outside
synapses. Several studies have used NMDA receptor antagonists to interrupt this cellular pathology, but
NMDAR antagonists also produce side effects due to disruption of physiological synaptic communication.
Memantine, an NMDAR antagonist with preferential inhibition toward eNMDARs, has been tested in several
studies, but produced unsatisfactory results due to a narrow window of efficacy versus toxicity. To circumvent
this problem, we recently developed a first-in-class exclusive antagonist of eNMDARs by attaching memantine
via polymer linkers to a gold (Au) nanoparticle, so that the resulting gold-memantine (AuM) nanotherapeutic is
too large to gain access to the synaptic cleft, and thus is restricted to extrasynaptic regions where it will
preferentially inhibit eNMDARs. Our preliminary studies of AuM demonstrate that AuM achieves potent
neuroprotection in primary neuron models of HD, ischemic stroke, and Alzheimer’s disease, and we validated
intracerebroventricular injection of AuM as a viable in vivo therapy in a pilot preclinical trial in BAC-HD mice.
Based upon these exciting results, we propose to evaluate AuM as a treatment for HD. In Phase I, we will
validate the utility of AuM as a therapy for HD by producing AuM in sufficient quantity and potency, by confirming
AuM action against eNMDAR toxicity in primary neuron models of HD, and by establishing proof-of-concept
efficacy of AuM in a pilot study in HD mice. If we achieve a set of objectives, quantitative milestones, we will
proceed to Phase II, where we will complete pharmacokinetics and pharmacodynamics studies to ascertain the
optimal AuM dosage and administration routes for a preclinical trial of AuM in HD N171-82Q mice. The ultimate
goal of this project will be to determine if AuM is capable of significant neuroprotection in HD mice and patient
neurons, and thus should be considered for further development as a drug treatment for human HD.
项目总结
项目成果
期刊论文数量(0)
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{{ truncateString('ELENA MOLOKANOVA', 18)}}的其他基金
Alzheimer's disease and novel nanotherapeutics exclusively targeting extrasynaptic NMDA receptors
阿尔茨海默病和专门针对突触外 NMDA 受体的新型纳米疗法
- 批准号:
10584412 - 财政年份:2021
- 资助金额:
$ 51.85万 - 项目类别:
Alzheimer's disease and novel nanotherapeutics exclusively targeting extrasynaptic NMDA receptors
阿尔茨海默病和专门针对突触外 NMDA 受体的新型纳米疗法
- 批准号:
10384478 - 财政年份:2021
- 资助金额:
$ 51.85万 - 项目类别:
Evaluation of the therapeutic potential of exclusive antagonists of extrasynaptic NMDA receptors for the treatment of opioid use disorder
评估突触外 NMDA 受体的独家拮抗剂治疗阿片类药物使用障碍的治疗潜力
- 批准号:
10581405 - 财政年份:2019
- 资助金额:
$ 51.85万 - 项目类别:
Evaluation of the therapeutic potential of exclusive antagonists of extrasynaptic NMDA receptors for treatment of opioid use disorders
评估突触外 NMDA 受体的独家拮抗剂治疗阿片类药物使用障碍的治疗潜力
- 批准号:
9912345 - 财政年份:2019
- 资助金额:
$ 51.85万 - 项目类别:
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