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

基本信息

批准号：
10584412
负责人：
ELENA MOLOKANOVA
金额：
$ 5.66万
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：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10584412
关键词：
Address Affect Age Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Amyloid deposition Apoptotic Behavior Biological Markers Biological Sciences Brain Brain region CASP3 gene Categories Cellular Stress Clinical Clinical Trials Cognitive Data Dendritic Spines Disease Disease Progression Disease model Dose Drug Design Engineering Etiology Evaluation Excipients FDA approved Failure Glutamates Goals Gold Guidelines Inductively Coupled Plasma Mass Spectrometry Inflammation Injections Intranasal Administration Kidney Knock-in Mouse Lead Learning Link Liver Mediating Memantine Memory Meta-Analysis Modeling Molecular Mus N-Methyl-D-Aspartate Receptors NMDA receptor antagonist Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Nose Outcome Pathologic Pathology Pathway interactions Pharmaceutical Preparations Phase Phenotype Polymers Positioning Attribute Prevention Protocols documentation Role Route Senile Plaques Signal Pathway Signal Transduction Synapses Synaptic Cleft Tauopathies Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect Transgenic Mice abeta oligomer antagonist apolipoprotein E-4 base behavior test brain tissue clinically relevant cognitive function cohort excitotoxicity extracellular hyperphosphorylated tau mouse model nanoparticle nanotherapeutic neuron loss neuropathology neuroprotection novel novel therapeutics power analysis preclinical study preclinical trial response side effect socioeconomics tau Proteins tau aggregation therapeutic evaluation

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a devastating socioeconomic impact. The failure rate in AD clinical trials is still ~99%, and the goal of finding efficient drugs that can stop and/or reverse the course of AD remains elusive so far. One of the reasons for these failures is a multifactorial nature of AD which makes it is very challenging to identify the “right” target for efficient therapeutic intervention. NMDA receptors (NMDARs) represent one of just two targets that were clinically validated in AD patients. Therapeutic doses of memantine, an NMDAR antagonist approved by the FDA for treatment of moderate-to- severe AD, were shown to delay the AD progression for 12 weeks and inhibit disruption of spatial learning through prevention of glutamatergic excitotoxicity triggered by elevated extracellular tonic glutamate levels leading to activation of extrasynaptic NMDARs (eNMDARs). However, meta-analysis of the memantine’s effects shows that memantine produces modest, short-lived, and highly heterogeneous clinical response. Administering memantine at higher concentrations or during the earlier AD stages is not an option because memantine may trigger serious psychomimetic side effects associated with the block of normal brain activity mediated by synaptic NMDARs (sNMDARs). Focusing efforts on drugs that block eNMDARs but not sNMDARs will avoid side effects associated with NMDAR antagonists, while producing an enhanced disease-modifying neuroprotective therapy. To address the critical need for exclusive antagonists of eNMDARs, we applied the rational drug design and engineered a nanotherapeutic (AuM) that is sufficiently large to be excluded from the synaptic cleft, thus, sparing sNMDARs, but still small enough to efficiently penetrate the brain tissues, reaching and blocking eNMDARs. We found that exclusive eNMDAR antagonists provide much stronger neuroprotection than memantine in several models associated with glutamatergic excitotoxicity, including protection of dendritic spines from Aβ oligomers. Based upon these exciting results, we propose to conduct an extensive evaluation of our exclusive eNMDAR antagonist AuM in two complementary AD models: 5X-FAD mice, a model of AD-related amyloid deposition, and P301S tau × ApoE4 homozygous knock-in mice, a tauopathy model. We will compare AuM-treated mice to vehicle-treated mice for disease-relevant read-outs and outcomes, tailored respectively to each model, including behavior (memory/learning), accumulation of amyloid plaques or tau tangles, microglial activation/function, CSF biomarkers, and neuropathology. We also propose to evaluate the feasibility of nose-to-brain delivery of AuM with the goal of establishing a clinically relevant route for our nanotherapeutic. Specifically, we will determine the time course of AuM distribution in 5XFAD mice after either direct intra-brain delivery or intranasal administration. The data acquired during this project will allow us to develop the efficient strategy to pursuit of IND-enabling studies for exclusive antagonists of eNMDARs for treatment of AD.

项目概要阿尔茨海默病（AD）是一种进行性神经退行性疾病，具有毁灭性的社会经济影响 AD临床试验的失败率仍约为99%，目标是寻找能够阻止AD的有效药物。和/或扭转 AD 的进程迄今为止仍然难以捉摸，这些失败的原因之一是多因素的。 AD 的本质使得确定有效治疗干预的“正确”目标非常具有挑战性。 NMDA 受体 (NMDAR) 是在 AD 患者中经过临床验证的仅有的两个靶标之一。治疗剂量的美金刚（一种 NMDAR 拮抗剂）经 FDA 批准用于治疗中度至严重 AD 时，被证明可以延迟 AD 进展 12 周并抑制空间学习的破坏通过预防细胞外强直性谷氨酸水平升高引发的谷氨酸兴奋性毒性导致突触外 NMDAR (eNMDAR) 的激活然而，美金刚效应的荟萃分析。表明美金刚产生适度、短暂且高度异质的临床反应。较高浓度的美金刚或在 AD 早期阶段不是一种选择，因为美金刚可能会引发严重的拟心理副作用，与突触介导的正常大脑活动受阻有关 NMDAR (sNMDAR) 的重点是阻断 eNMDAR 而不是 sNMDAR 的药物将避免副作用。与 NMDAR 拮抗剂相关，同时产生增强的缓解疾病的神经保护疗法。为了满足对 eNMDAR 独家拮抗剂的迫切需求，我们应用了合理的药物设计和设计了一种足够大的纳米治疗剂（AuM），可以将其排除在突触间隙之外，从而避免 sNMDAR，但仍然足够小，可以有效穿透脑组织，到达并阻止 eNMDAR。发现独特的 eNMDAR 拮抗剂在多种疾病中提供比美金刚更强的神经保护作用与谷氨酸兴奋性毒性相关的模型，包括保护树突棘免受 Aβ 寡聚物的影响。基于这些令人兴奋的结果，我们建议对我们独家的 eNMDAR 进行广泛的评估两种互补 AD 模型中的拮抗剂 AuM：5X-FAD 小鼠，AD 相关淀粉样蛋白沉积模型，以及 P301S tau × ApoE4 纯合敲入小鼠，一种 tau 蛋白病模型，我们将与 AuM 治疗的小鼠进行比较。媒介物治疗小鼠的疾病相关读数和结果，分别针对每个模型进行定制，包括行为（记忆/学习）、淀粉样斑块或 tau 蛋白缠结的积累、小胶质细胞激活/功能、脑脊液我们还建议评估从鼻子到大脑输送 AuM 的可行性。具体来说，我们将确定我们的纳米治疗的临床相关途径。直接脑内给药或鼻内给药后 5XFAD 小鼠中 AuM 分布的时间过程。该项目期间获得的数据将使我们能够制定有效的策略来追求 IND 支持 eNMDAR 独家拮抗剂治疗 AD 的研究。