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.

项目概要亨廷顿病 (HD) 是一种遗传性 CAG-聚谷氨酰胺重复扩张神经退行性疾病 HD 的特点是认知和精神障碍，与突触功能障碍和神经元相关。 HD 中大脑皮质纹状体系统的丧失，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 (eNMDAR) 的激活有关一些研究已经使用 NMDA 受体拮抗剂来中断这种细胞病理学，但是 NMDAR 拮抗剂还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，已在多个试验中进行了测试研究，但由于功效与毒性的窗口较窄，结果并不令人满意。针对这个问题，我们最近开发了一种首创的 eNMDAR 独家拮抗剂，通过附加美金刚通过聚合物连接体连接到金 (Au) 纳米颗粒，从而得到金美金刚 (AuM) 纳米治疗药物太大而无法进入突触间隙，因此仅限于突触外区域我们对 AuM 的初步研究表明，AuM 具有有效的抑制作用。 HD、缺血性中风和阿尔茨海默病的原代神经元模型中的神经保护作用，我们验证了在 BAC-HD 小鼠的临床前试验中，脑室内注射 AuM 作为一种可行的体内疗法。基于这些令人兴奋的结果，我们建议在第一阶段评估 AuM 作为 HD 的治疗方法。通过生产足够数量和效力的 AuM，验证 AuM 作为 HD 治疗的效用，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 小鼠试点研究中的功效如果我们实现了一系列目标、定量里程碑，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，以确定在 HD N171-82Q 小鼠中进行 AuM 临床前试验的 AuM 最佳剂量和给药途径最终。该项目的目标是确定 AuM 是否能够对 HD 小鼠和患者提供显着的神经保护作用神经元，因此应考虑进一步开发作为人类 HD 的药物治疗。