Pre-Clinical Evaluation of a Rationally Designed Nanotherapeutic for Huntington's Disease

项目摘要 亨廷顿病（Huntington 'sdisease，HD）是一种遗传性CAG-多聚谷氨酰胺重复序列扩增的神经退行性疾病 以认知和精神障碍为特征。HD与突触功能障碍和神经元损伤相关。 大脑皮质纹状体系统的缺失。在HD中，神经元对多巴胺能的敏感性增加， 兴奋性毒性与位于突触外的突触外NMDA受体（eNMDAR）的激活有关。 突触几项研究已经使用NMDA受体拮抗剂来中断这种细胞病理学，但 NMDAR拮抗剂还由于生理突触通信的中断而产生副作用。 美金刚是一种对eNMDAR具有优先抑制作用的NMDAR拮抗剂，已在几个实验中进行了测试。 研究，但产生不令人满意的结果，由于一个狭窄的窗口的疗效与毒性。规避 这个问题，我们最近开发了一种一流的独家拮抗剂eNMDAR连接美金刚 通过聚合物连接体连接到金（Au）纳米颗粒，使得所得的金-美金刚（AuM）纳米颗粒 太大而不能进入突触间隙，因此被限制在突触外区域，在那里它将 优先抑制eNMDAR。我们对AuM的初步研究表明，AuM具有很强的 在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， 脑室内注射AuM作为BAC-HD小鼠中的先导临床前试验中的可行体内疗法。 基于这些令人兴奋的结果，我们建议评估AuM作为HD的治疗。在第一阶段，我们将 通过以足够的量和效力生产AuM，通过确认 在HD的原代神经元模型中AuM对eNMDAR毒性的作用，并通过建立概念验证 在HD小鼠中的初步研究中的AuM的功效。如果我们实现了一系列目标，量化的里程碑，我们将 进入II期，我们将完成药代动力学和药效学研究，以确定 HD N171- 82 Q小鼠中AuM临床前试验的最佳AuM剂量和给药途径。最终 本项目的目标是确定AuM是否能够在HD小鼠和患者中具有显著的神经保护作用。 神经元，因此应考虑进一步开发作为人类HD的药物治疗。

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.