Alzheimer's disease drug development

阿尔茨海默病药物开发

• 批准号: 10688806
• 负责人: Nigel H. Greig
• 金额: $ 24.02万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688806
• 关键词: 3xTg-AD mouse; Acute; Adult; Adverse effects; Affect; Age; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Apolipoprotein E; Behavioral; Biological; Blood Vessels; Brain; COVID-19; Cell Death; Cells; Cerebrovascular system; Chemistry; Chronic; Clinical; Clinical Drug Development; Clinical Research; Clinical Trials; Cognitive deficits; Complex; DNA Damage; Degenerative Disorder; Dementia; Deposition; Detection; Development; Disease; Disease Progression; Dose; Drug Design; Drug Targeting; Elderly; Elements; Embryo; Europe; Event; Excision; Failure; Fostering; Generations; Genes; Genetic Transcription; Government; Growth; Human; Image Analysis; Immunomodulators; Impairment; Infiltration; Inflammation; Inflammatory; Interdisciplinary Study; Interruption; Intervention; Intramural Research Program; Investigational Therapies; Laboratories; Legal patent; Libraries; Licensing; Lipid Peroxidation; Lymphocyte; MAPT gene; Maintenance; Mediating; Messenger RNA; Microglia; Mitochondrial DNA; Modeling; Modification; Mus; Mutation; National Institute on Aging; Nature; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurology; Neuronal Dysfunction; Neurons; Organ; Oxidants; Oxidative Stress; Pathology; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Population; Positron-Emission Tomography; Process; Production; Protein Precursors; Proteins; Psychiatry; Reactive Oxygen Species; Reporting; Research; Research Project Grants; Rodent; Role; Sedation procedure; Serum; Structure-Activity Relationship; Symptoms; Synapses; TNF gene; Teratogens; Thalidomide; Therapeutic Intervention; Time; Toxic effect; Translating; Translations; United States National Institutes of Health; Variant; Vertebral column; Work; aging brain; analog; behavioral impairment; bench-to-bedside translation; cerebral atrophy; clinical development; course development; cytokine; cytokine release syndrome; design; drug candidate; drug development; entorhinal cortex; familial Alzheimer disease; glucagon-like peptide 1; in utero; in vivo; inhibitor; interest; mouse model; nervous system disorder; neuroinflammation; neuron loss; neuropathology; neurotoxic; normal aging; novel; novel therapeutics; phenserine; pomalidomide; pre-clinical; preclinical study; presenilin; presenilin-1; programs; protein aggregation; protein oligomer; proteostasis; resilience; response; small molecule; tau Proteins; therapeutic candidate; 3xTg-AD mouse; Acute; Adult; Adverse effects; Affect; Age; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Apolipoprotein E; Behavioral; Biological; Blood Vessels; Brain; COVID-19; Cell Death; Cells; Cerebrovascular system; Chemistry; Chronic; Clinical; Clinical Drug Development; Clinical Research; Clinical Trials; Cognitive deficits; Complex; DNA Damage; Degenerative Disorder; Dementia; Deposition; Detection; Development; Disease; Disease Progression; Dose; Drug Design; Drug Targeting; Elderly; Elements; Embryo; Europe; Event; Excision; Failure; Fostering; Generations; Genes; Genetic Transcription; Government; Growth; Human; Image Analysis; Immunomodulators; Impairment; Infiltration; Inflammation; Inflammatory; Interdisciplinary Study; Interruption; Intervention; Intramural Research Program; Investigational Therapies; Laboratories; Legal patent; Libraries; Licensing; Lipid Peroxidation; Lymphocyte; MAPT gene; Maintenance; Mediating; Messenger RNA; Microglia; Mitochondrial DNA; Modeling; Modification; Mus; Mutation; National Institute on Aging; Nature; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurology; Neuronal Dysfunction; Neurons; Organ; Oxidants; Oxidative Stress; Pathology; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Population; Positron-Emission Tomography; Process; Production; Protein Precursors; Proteins; Psychiatry; Reactive Oxygen Species; Reporting; Research; Research Project Grants; Rodent; Role; Sedation procedure; Serum; Structure-Activity Relationship; Symptoms; Synapses; TNF gene; Teratogens; Thalidomide; Therapeutic Intervention; Time; Toxic effect; Translating; Translations; United States National Institutes of Health; Variant; Vertebral column; Work; aging brain; analog; behavioral impairment; bench-to-bedside translation; cerebral atrophy; clinical development; course development; cytokine; cytokine release syndrome; design; drug candidate; drug development; entorhinal cortex; familial Alzheimer disease; glucagon-like peptide 1; in utero; in vivo; inhibitor; interest; mouse model; nervous system disorder; neuroinflammation; neuron loss; neuropathology; neurotoxic; normal aging; novel; novel therapeutics; phenserine; pomalidomide; pre-clinical; preclinical study; presenilin; presenilin-1; programs; protein aggregation; protein oligomer; proteostasis; resilience; response; small molecule; tau Proteins; therapeutic candidate

Overview: Evidence from clinical and preclinical studies indicates that basal inflammatory status increases as a function of normal aging, and progressive development of a mild pro-inflammatory state closely associates with the major degenerative diseases of the elderly (Holmes et al., Neurology 73:768-74, 2009; Heneka et al., Lancet Neurol 14:388-405, 2015). Hallmarks of aging include increased oxidative stress, lipid peroxidation and mitochondrial and DNA damage, particularly in brain. Microarray studies indicate a rise in inflammatory and pro-oxidant genes with a decline in growth, anti-inflammatory and anti-oxidant genes in the brain of older vs. adult rodents (Cribbs et al., J Neuroinflammation 9:179, 2012). In line with this, levels of brain pro-inflammatory cytokines are elevated with age in rodents and humans, and several regulatory molecules and anti-inflammatory cytokines reduced (Deleidi et al., Front Neurosci 9:172, 2015). Microglia are implicated as the major culprit of this ensuing neuroinflammation. Correcting the overproduction of pro-inflammatory cytokines by microglia may mitigate a broad number of neurodegenerative disorders prevalent in the elderly, and, in particular Alzheimers disease (AD). However, finding an appropriate drug target to safely and effectively achieve this has thus far proved difficult, and likely accounts for many of the numerous failures of clinical trials of anti-inflammatory agents in AD and associated disorders. Tumor necrosis factor-alpha (TNF) is a key pro-inflammatory cytokine generated by microglia. On release, TNF may initiate a self-propagating cycle of unchecked inflammation (Jung et al., Front Cell Dev Biol 7:313, 2019). Pharmacologic intervention to interrupt this cycle may be beneficial in the setting of neuroinflammation-mediated diseases. In 1993, Moreira et al. (J Exp Med 177:1675-80, 1993) described studies showing that the drug thalidomide (THAL) was able to lower TNF protein levels post-transcriptionally by accelerating degradation of its mRNA. Unfortunately, THAL is not a particularly potent TNF lowering agent and is associated with serious teratogenic adverse effects to embryos in utero, sedation and peripheral neuropathy at clinical doses (Calabrese & Fleischer, Am J Med 108:487-95, 2000; DeCourt et al., Curr Alzheimer Res 14:403-411, 2017). Nevertheless, the observation of THALs TNF lowering activity supported studies to differentiate these actions, understand THALs TNF structure/activity relationship and develop more potent analogs. In principle, the identification of analogs with enhanced anti-TNF activity and reduced teratogenic and neurotoxic effects may provide a viable treatment for neuroinflammatory and other inflammatory diseases. Our chemistry modifications to the backbone of THAL and newer analogs (namely pomalidomide (POM)) have generated a library of novel agents (US patents: 7,973,057 and 8,927,725, and Application No. 62/235,105). Our focus is to identify well-tolerated drug-like compounds with more potent anti-TNF activity from our generated library, and develop these as experimental drugs to characterize the role of the neuroinflammatory component in and to treat AD and associated disorders. Problem/Focused Aims: AD is a complex disorder that manifests as progressive dementia with few other symptoms. With a long meandering course, AD is associated with deposits of amyloid-beta protein (AB) of 40 and 42 amino acids as much as 20 years prior to development of dementia. It also induces intracellular accumulation of the microtubule-associated protein Tau (MAPT) as neurofibrillary tangles (NFTs) that correlate more closely with the extent of dementia (Sambamurti et al. Curr Alzheimer Res 3:81-90, 2006; Baranello et al. Curr Alzheimer Res 12:32-46, 2015). NFTs arise some 10 years after AB, and brain atrophy follows after 5 more years. However, the resilience and redundancy of the nervous system protects affected subjects from dementia for approx. 5 further years after the detection of atrophy by brain image analysis. The discovery that familial AD (FAD) mutations in AB precursor protein (APP) and presenilins (PSEN1) and 2 (PSEN2) increase AB42, have placed amyloid at the Occams razor of AD. The finding that the E4 variant of apolipoprotein E (APOE), detected in almost half the AD population, also fosters AB deposition further boosts the amyloid hypothesis. Despite the consistency of this finding, the time-dependent AB-triggered mechanisms of neuronal dysfunction and degeneration remain unclear; thereby making therapeutic intervention difficult. As AB oligomers and aggregates are tolerated over an extended time, their toxicity may not be the direct cause of neurodegeneration but, instead, an initiator of a cascade of events that become self-propagating and then drive AD progression. This premise may account for the failure of anti-amyloid therapies in clinical trials when administered late in the disease course (Becker et al., Nature Rev Drug Discov 13:156, 2014). The presence of soluble and insoluble AB and MAPT can induce microglia activation (McGeer Acta Neuropathol 126:479-97, 2013), and direct evidence of neuroinflammation in AD brain has been shown by in vivo PET imaging (Schuitemaker et al., Neurobiol Aging 34:12836, 2013). Notably, levels of pro-inflammatory cytokines are elevated in serum and CSF from AD patients, for TNF by as much as 25-fold (Tarkowski et al., J Clin Immunol 19:223-30, 1999). In MCI subjects that progress to develop AD, a rise in CSF TNF correlates with disease progression (Tarkowski et al., J Neurol Neurosurg Psychiatry 74:1200-5, 2003). Paralleling this, elevated expression of TNF is reported in the entorhinal cortex of 3xTg-AD mice prior to amyloid and tau pathology, and this increase associates with the onset of cognitive deficits in these mice and to later neuronal loss (Janelsins et al. J Neuroinflamm 2:23, 2005). We postulate that failure of protein homeostasis leads to accumulation of proteins (e.g., AB, APOE, MAPT) that induce microglial activation and a proinflammatory M1 response to instigate their removal. A continuing generation of protein (AB, APOE, MAPT) leads to maintenance of a chronic M1 response, impairment of transition to an anti-inflammatory M2 response (particularly in aging brain already vulnerable to inflammation) with ensuing neuronal impairment observed in animal models and in preclinical AD, which ultimately leads to cell death. Proinflammatory cytokines, like TNF, induce vascular changes to allow lymphocyte infiltration that may underpin reported cerebral vasculature leakiness of AD patients and related Tg mouse models. Moreover, TNF induces AB production in cellular and animal AD models, further increasing its accumulation and the entire cascade. Our focus is elucidate the time course of development of neuropathology accumulation of inflammatory cytokines and behavioral deficits in unique mouse models that may reflect the disease pathology more than the currently available ones. We also evaluate the treatment of these deficits with a clinically approved immunomodulator, POM, which lowers TNF generation as well as with the new more potent small molecule TNF synthesis inhibitors generated and patented for NIH by our research collaborative group within the Intramural Research Program of NIA. Our research has highlighted thionated analogs of POM as new AD therapeutic candidates that mitigate neuroinflammation, neuronal loss and behavioral impairments in AD cellular/animal models. Using the same models, the drug Phenserine likewise appears highly promising in mitigating programmed neuronal cell death/inflammation. We have extended our studies to evaluate these same compounds in models associated with COVID-19, as a 'cytokine storm' appears to be instigated across organs, including brain, in this disorder also.

概述：来自临床和临床前研究的证据表明，基础炎症状态的增加是正常衰老的函数，以及与老年人的主要退化性疾病紧密相关的轻度促炎状态的逐步发展（Holmes等人，Neurology，Neurology 73：768-74，2009; Heneka et al.Heneka et al al.neurol neurol neurol neurol neurol neurol neurol neurol neurol。衰老的标志包括增加氧化应激，脂质过氧化以及线粒体和DNA损伤，尤其是在大脑中。 微阵列研究表明，炎症和促氧化剂基因的升高，在老年啮齿动物与成年啮齿动物的大脑中生长，抗炎和抗氧化基因的生长下降（Cribbs等，J Neurouinflammation 9：179，2012）。与此一致，随着啮齿动物和人类的年龄，脑促炎细胞因子的水平升高，几种调节分子和抗炎细胞因子降低（Deleidi等人，前神经科学9：172，2015）。小胶质细胞被认为是这种随之而来的神经炎症的主要罪魁祸首。通过小胶质细胞纠正促炎性细胞因子的过量生产可能会减轻老年人普遍存在的广泛的神经退行性疾病，尤其是阿尔茨海默氏病（AD）。但是，找到适当的药物靶标以安全有效地实现这一目标已被证明是困难的，并且很可能会说明AD和相关疾病中抗炎药的临床试验众多失败中的许多失败。 肿瘤坏死因子-Alpha（TNF）是小胶质细胞产生的关键促炎细胞因子。发行后，TNF可能会引发未检查的炎症的自传播周期（Jung等人，前细胞Dev Biol 7：313，2019）。中断此周期的药理学干预措施在神经炎症介导的疾病的情况下可能是有益的。 1993年，Moreira等。 （J Exp Med 177：1675-80，1993）描述的研究表明，沙利度胺（Thal）能够通过加速其mRNA降解后转录后降低TNF蛋白水平。不幸的是，THAL并不是一种特别有效的TNF降低剂，并且与临床剂量的子宫，镇静和外围神经性胚胎的严重致变性不良反应有关（Calabrese＆Fleischer，AM J Med 108：487-95，2000; Decourt等，Decourt等，Curr alzheimerers res 14：403-114：403-11，然而，观察到降低活性的thals tnf支持研究，以区分这些动作，了解Thals TNF结构/活动关系并发展出更有效的类似物。原则上，鉴定具有增强抗TNF活性的类似物以及降低的破坏性和神经毒性作用可能为神经炎症和其他炎症性疾病提供可行的治疗方法。我们对Thal和较新类似物（即Pomalidomide（POM））的骨干的化学修饰已经产生了新型药物库（美国专利：7,973,057和8,927,725，以及应用程序号62/235,105）。我们的重点是从我们生成的文库中鉴定具有更有效的抗TNF活性的耐受性良好的药物样化合物，并将其作为实验药物开发，以表征神经炎性成分在AD和相关疾病中的作用。 问题/重点目的：AD是一种复杂的疾病，表现为进行性痴呆，几乎没有其他症状。在漫长的曲折过程中，AD与40和42个氨基酸的淀粉样蛋白蛋白质（AB）的沉积有关，直到痴呆发育前20年。它还诱导微管相关蛋白tau（MAPT）作为神经原纤维缠结（NFT）的细胞内积累，与痴呆症的程度更紧密地相关（Sambamurti等人。 NFT发生在AB后约10年，大脑萎缩在5年后跟随。但是，神经系统的韧性和冗余可保护受影响的受试者免受痴呆症。通过大脑图像分析检测萎缩后5年。 AB前体蛋白（APP）和Presenilins（PSEN1）和2（PSEN2）增加AB42中的家族性AD（FAD）突变的发现已将淀粉样蛋白放在AD的Occams Razor上。在几乎一半的AD人群中检测到的载脂蛋白E（APOE）的E4变体的发现，也促进AB沉积进一步增强了淀粉样假说。尽管有这一发现的一致性，但依赖于时间依赖的神经元功能障碍和变性的机制仍不清楚。从而使治疗干预变得困难。随着AB低聚物和聚集体在很长的时间内被耐受性，它们的毒性可能不是神经变性的直接原因，而是成为级联事件的发​​起者，这些事件变得自我传播，然后驱动AD的进展。该前提可能解释抗淀粉样疗法在疾病课程后期进行临床试验中的抗淀粉样疗法（Becker等人，Nature Rev Drug Discov 13：156，2014）。可溶性和不溶性AB和MAPT的存在可以诱导小胶质细胞激活（McGeer Acta Neuropathol 126：479-97，2013），AD脑中神经炎症的直接证据已由Intenmaker Imaging显示（Schuitemaker等人，Neurobiol Aging 34：12836，2013，2013，2013）。值得注意的是，AD患者的血清和CSF的促炎细胞因子水平升高，TNF的水平高达25倍（Tarkowski等人，J Clin Immunol 19：223-30，1999）。在发展为AD的MCI受试者中，CSF TNF的增加与疾病的进展相关（Tarkowski等，J Neurol Neurol Neurosurg Psychiatry 74：1200-5，2003）。在淀粉样蛋白和tau病理学之前的3xTG-AD小鼠的内嗅皮层中，TNF的表达升高，与这些小鼠的认知缺陷和后来的神经元损失相关（Janelsins等人，Jeuroloinflamm 2：23，2005）。 我们假设蛋白质稳态的失败会导致蛋白质（例如AB，ApoE，MAPT）的积累，从而诱导小胶质细胞激活和促炎M1反应以激发其去除。持续产生的蛋白质（AB，APOE，MAPT）可维持慢性M1反应，过渡到抗炎M2反应的过渡（尤其是在已经容易发生炎症的衰老大脑中），随后在动物模型中观察到的神经元损伤以及在临床上观察到的神经元损伤，最终导致细胞死亡。促炎细胞因子（如TNF）会诱导血管变化，以使淋巴细胞浸润，可能支撑的淋巴细胞浸润可能报告了AD患者的脑血管泄漏和相关的TG小鼠模型。此外，TNF在细胞和动物AD模型中诱导AB产生，进一步增加了其积累和整个级联。我们的重点是阐明在独特的小鼠模型中炎症细胞因子和行为缺陷的神经病理学积累的时间过程，这些模型可能比目前可用的病理更多地反映了疾病病理。我们还通过临床认可的免疫调节剂POM评估了这些缺陷的治疗方法，POM降低了TNF的产生以及新的更有效的小分子TNF合成抑制剂，并在NIA室内研究计划中为NIA的NIH生成并为NIH授权了NIH。 我们的研究强调了POM的类似物，作为缓解神经炎症，神经元丧失和AD细胞/动物模型中的神经炎症损失和行为障碍的新AD治疗候选者。使用相同的模型，药物保氨酸同样在缓解程序性神经元细胞死亡/炎症方面似乎很有希望。我们已经扩展了研究，以评估与Covid-19相关的模型中的这些相同化合物，因为“细胞因子风暴”似乎也在包括大脑在内的跨器官中煽动了这种疾病。