Targeting ApoE4 as a Therapeutic Strategy for Alzheimer's Disease

以 ApoE4 为靶点作为阿尔茨海默病的治疗策略

基本信息

批准号：
8549072
负责人：
ROBERT W. MAHLEY
金额：
$ 81.86万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549072
关键词：
Accounting Affect Age Age of Onset Alzheimer&apos s Disease Amyloid beta-Protein Precursor Animal Model Apolipoprotein E Behavioral Binding Biological Assay Biological Availability Brain Canis familiaris Cardiovascular system Cells Cerebrospinal Fluid Chemicals Chemistry Clinical Clinical Research Cognitive Cognitive deficits Community Healthcare Data Dependency Development Disease Progression Documentation Dose Drug Formulations Drug Kinetics Event Excretory function Family Fluorescence Resonance Energy Transfer Functional disorder Future Goals Grant Health Care Costs Human Impaired cognition Impairment In Vitro Individual Investigational Drugs Lead Learning Libraries Measures Mediating Memory impairment Metabolism Microsomes Mitochondria Modeling Molecular Conformation Mus Mutant Strains Mice Nerve Degeneration Neurites Neurodegenerative Disorders Neuron-Specific Enolase Neurons No-Observed-Adverse-Effect Level Oral Pathology Patients Penetration Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Property Protein Isoforms Proteins Rattus Research Risk Role Safety Senile Plaques Series Specificity Structure Structure-Activity Relationship Synapses Technology Testing Therapeutic Toxic effect Toxicology Transgenic Mice absorption analog apolipoprotein E-3 apolipoprotein E-4 base design drug metabolism efficacy testing genetic risk factor high throughput screening improved in vivo meetings mitochondrial dysfunction mouse model neuropathology neurotoxic neurotoxicity novel pharmacophore pre-clinical preclinical study prevent programs protein structure public health relevance respiratory safety testing small molecule

项目摘要

DESCRIPTION (provided by applicant): Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), and apoE4 carriers account for 65-80% of AD cases. ApoE4 increases the occurrence and lowers the age of onset of AD, and considerable evidence suggests that it has a fundamental role in the neurodegeneration and pathophysiology of AD. We showed that apoE4, because of its unique structural feature referred to as apoE4 domain interaction, is highly susceptible to proteolytic cleavage in neurons, generating neurotoxic fragments. The primary toxic fragment, apoE4(1-272), is found at much higher levels in the brain and cerebrospinal fluid of AD patients than non-demented individuals and in transgenic mice expressing human apoE4 in neurons. These transgenic mice have learning and memory impairments and neuropathology, including loss of synaptodendritic connections, which correlates with the onset of learning deficits. The toxicity induced by apoE4 and apoE4(1-272) is mediated by their inhibition of mitochondrial function, an initial event leading to neurodegeneration and cognitive impairment in AD. Thus, a number of studies have validated apoE4 as an excellent target for AD drugs. We discovered small molecules that bind apoE4 to modify the protein's structure to reduce domain interaction and proteolytic cleavage to prevent its toxicity. Our lead apoE4 structure corrector (apoE4SC), PY-101, protects neurons from apoE4-induced mitochondrial toxicity and reverses the impairment of neurite outgrowth in vitro. In vivo, PY-101 has good pharmacokinetics (PK) and brain bioavailability, blocks formation of toxic apoE4(1-272) in neuron-specific enolase (NSE)-apoE4 transgenic mouse brain, and protects against mitochondrial impairment in brain, an initial event in disease progression in AD. In this U01 grant, we propose to conduct the preclinical studies to evaluate the efficacy of PY-101 as a unique drug to treat AD. We will test PY-101 for efficacy in blocking cognitive impairment and neuropathology in the NSE-apoE4 and APP/apoE4 animal models of AD to validate PY-101 as a drug to treat AD. In addition, we will focus on optimizing the properties of apoE4SCs using our pharmacophore model based on the structure-activity relationship around PY-101. We will use this model to build a chemical optimization program around a novel chemical series to improve the potency of our prototypical apoE4SC while maintaining good PK and high brain penetration. Using the model, medicinal chemistry, and our high-throughput screening assays, we will optimize the efficacy and pharmaceutical properties of our apoE4SCs. To do this, small molecules will be screened against our primary GFP-apoE4-eDHFR FRET assay, which measures target engagement and the ability to disrupt apoE4 domain interaction to increase apoE4 stability. Optimized apoE4SCs will be subjected to stability, PK, and pharmacodynamic studies to select leads to test for efficacy in AD mouse models. The lead apoE4SC will be subjected to standard investigational new drug-enabling preclinical development with a goal of initiating clinical studies to test for safety and efficacy in treating D and proceeding to an IND.

描述（由申请人提供）：载脂蛋白（APO）E4是阿尔茨海默氏病（AD）的主要遗传危险因素，而APOE4载体占AD病例的65-80％。 APOE4增加了发生的发生并降低了AD的发作年龄，并且有大量证据表明，它在AD的神经变性和病理生理学中具有基本作用。我们表明，由于APOE4具有独特的结构特征，称为APOE4结构域相互作用，因此在神经元中高度易受蛋白水解裂解的影响，从而产生神经毒性片段。与非痴呆的个体以及在神经元中表达人apoE4的转基因小鼠相比，在大脑和脑脊液中发现了主要的毒性片段APOE4（1-272）。这些转基因小鼠具有学习和记忆力障碍和神经病理学，包括失去突触的连接，这与学习缺陷的发作相关。 APOE4和APOE4（1-272）诱导的毒性是由它们抑制线粒体功能的介导的，这是导致AD神经变性和认知障碍的初始事件。因此，许多研究已验证APOE4是AD药物的绝佳靶标。我们发现了结合APOE4的小分子以修饰蛋白质的结构，以减少域的相互作用和蛋白水解裂解以防止其毒性。我们的铅APOE4结构校正器（APOE4SC）PY-101可保护神经元免受APOE4诱导的线粒体毒性，并逆转体外神经突生长的损害。在体内，PY-101具有良好的药代动力学（PK）和脑生物利用度，阻塞了神经元特异性烯醇酶（NSE） - APOE4转基因小鼠脑中有毒APOE4（1-272）的形成，并保护脑部疾病中的初始疾病进展。在本U01赠款中，我们建议进行临床前研究，以评估PY-101作为治疗AD的独特药物的功效。我们将测试PY-101在阻断NSE-APOE4和APP/APOE4 AD动物模型中阻断认知障碍和神经病理学的功效，以验证PY-101作为治疗AD的药物。此外，我们将基于PY-101周围的结构 - 活性关系，使用我们的药效团模型来优化APOE4SC的特性。我们将使用该模型围绕一个新型的化学系列构建化学优化程序，以提高原型APOE4SC的效力，同时保持良好的PK和高脑穿透力。使用该模型，药物化学和我们的高通量筛选测定法，我们将优化APOE4SC的功效和药物特性。为此，将对我们的主要GFP-APOE4-EDHFR FRET分析进行筛选，该分子测量目标参与度以及破坏APOE4域相互作用以提高APOE4稳定性的能力。优化的APOE4SC将经过稳定性，PK和药效学研究，以选择AD小鼠模型中的功效测试。铅APOE4SC将受到标准研究的新型药物临床前开发的影响，其目的是启动临床研究，以测试治疗D并进入IND的安全性和功效。