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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：
ELENA MOLOKANOVA
金额：
$ 51.85万
依托单位：
NEURANO BIOSCIENCE
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：
https://reporter.nih.gov/project-details/10258489
关键词：
Alzheimer&apos s Disease Bacterial Artificial Chromosomes Biological Assay Brain Brain-Derived Neurotrophic Factor CAG repeat Calcium Cell Death Clinical Trials Code Cognitive Communication Corpus striatum structure Development Disease Dopamine D2 Receptor Electrophysiology (science)FDA approved Functional disorder Genes Glutamates Goals Gold Guidelines Hand Strength Health Human Huntington Disease Huntington gene Huntington protein Image Impaired cognition Impairment In Vitro Inherited Injections Interruption Involuntary Movements Ischemic Stroke Link Longevity Mediating Memantine Mental disorders Modeling Molecular Motor Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Outcome Pathogenesis Pathogenicity Patients Pharmacology Pharmacotherapy Phase Physiological Pilot Projects Play Polymers Predisposition Preparation Production Property RNA Role Route Synapses Synaptic Cleft System Testing Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Traumatic Brain Injury Trinucleotide Repeat Expansion Validation Work analytical method base cellular pathology cohort cytotoxicity design disease phenotype dosage efficacious treatment efficacy study excitotoxicity in vitro Assay in vivo in vivo Model insight mitochondrial dysfunction nanoparticle nanotherapeutic neuron loss neuropathology neuroprotection neurotoxicity novel pharmacokinetics and pharmacodynamics polyglutamine preclinical efficacy preclinical evaluation preclinical trial preservation prevent protein expression side effect stem synaptic inhibition therapy 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