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.

项目摘要阿尔茨海默氏病（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临床试验中的失败率仍然约为99％，目的是找到可以停止的有效药物到目前为止，/或扭转广告过程仍然难以捉摸。这些失败的原因之一是多因素 AD的性质使确定有效治疗干预的“正确”目标是非常挑战。 NMDA受体（NMDAR）是AD患者临床验证的两个目标之一。纪念碑的治疗剂量，NMDAR的拮抗剂已获得FDA的批准严重的AD显示会延迟AD的进展12周，并抑制空间学习的破坏通过预防谷氨酸能兴奋性，由升高的细胞外强调水平触发导致激活外突触NMDAR（ENMDAR）。但是，对纪念效果的荟萃分析表明纪念碑会产生适度，短暂且高度异质的临床反应。管理美容以较高的浓度或在较早的广告阶段不可行，因为美容可以触发与突触介导的正常脑活动相关的严重心理副作用 NMDARS（SNMDARS）。将精力集中在阻止enmdars而不是SNMDAR的药物上，将避免副作用与NMDAR拮抗剂相关，同时产生改善疾病的神经保护疗法。为了满足对Enmdars独家拮抗剂的关键需求，我们应用了合理的药物设计和设计了一个足够大的纳米疗法（AUM） SNMDAR，但仍然足够小，可以有效地穿透脑组织，伸入和阻塞enmdars。我们发现独家的enmdar拮抗剂提供的神经保护作用比美金刚在几个与谷氨酸能兴奋性毒性相关的模型，包括保护树突状刺激Aβ低聚物。基于这些令人兴奋的结果，我们建议对我们的独家Enmdar进行广泛的评估两种完整的AD模型中的拮抗剂AUM：5倍FAD小鼠，一种与AD相关的淀粉样蛋白沉积模型和 p301s tau×apoE4纯合敲入小鼠，一种tauopathy模型。我们将将经AUM处理的小鼠与与疾病相关的读出和结果的车辆处理的小鼠，分别针对每个模型量身定制行为（记忆/学习），淀粉样斑块或tau缠结的积累，小胶质激活/功能，CSF 生物标志物和神经病理学。我们还建议评估AUM的鼻子到脑递送的可行性目的是为我们的纳米疗法建立临床相关的途径。具体来说，我们将确定直接脑内递送或鼻内给药后，AUM分布的时间过程。该项目中获得的数据将使我们能够制定有效的策略来追求索引 enmdar的独家拮抗剂用于治疗AD的研究。