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

• 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
• 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' 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

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 亨廷顿病(HD)是一种遗传性CAG-多谷氨酰胺重复扩张型神经退行性疾病 以认知和精神障碍为特征的。HD与突触功能障碍和神经元相关 大脑皮质纹状体系统的缺失。HD患者神经元对谷氨酸能的敏感性增加 兴奋性毒性与位于外部的突触外NMDA受体的激活有关 突触。一些研究已经使用NMDA受体拮抗剂来阻断这种细胞病理，但 NMDAR拮抗剂也会因生理突触通讯中断而产生副作用。 美金刚是一种NMDAR拮抗剂，对eNMDAR具有优先抑制作用，已在几个 研究，但由于疗效与毒性的窗口狭窄，结果并不令人满意。绕过 为了解决这个问题，我们最近开发了一种一流的eNMDARs独家拮抗剂，通过附着美金刚 通过聚合物连接物连接到金(Au)纳米颗粒，从而得到的金-美金胺(AuM)纳米治疗 太大而无法接触到突触间隙，因此被限制在突触外区域 优先抑制eNMDAR。我们对AUM的初步研究表明，AUM实现了 HD、缺血性中风和阿尔茨海默病的初级神经元模型的神经保护，我们验证了 在BAC-HD小鼠的先导性临床前试验中，脑室内注射AuM作为一种可行的体内治疗方法。 基于这些令人兴奋的结果，我们建议评估AuM作为HD的一种治疗方法。在第一阶段，我们将 通过生产足够数量和效力的AUM来验证AUM作为HD治疗的有效性，通过确认 AUM在HD原代神经元模型中对抗eNMDAR毒性的作用，并通过建立概念验证 AUM在HD小鼠的先导性研究中的疗效。如果我们实现了一系列目标、量化的里程碑，我们将 进入第二阶段，我们将完成药代动力学和药效学研究，以确定 AUM在HD N171-82Q小鼠的临床前试验的最佳剂量和给药途径。终极的 该项目的目标将是确定AUM是否能够显著保护HD小鼠和患者的神经 因此，应该考虑将其进一步开发为治疗人类HD的药物。