Alzheimer's disease drug development

阿尔茨海默病药物开发

• 批准号: 10252547
• 负责人: Nigel H. Greig
• 金额: $ 142.81万
• 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/10252547
• 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; Amino Acids; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Apolipoprotein E; Appearance; Behavioral; Biological; Blood Vessels; Brain; Cell Death; Cells; Cerebrovascular system; 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; Modification; Mus; Mutation; National Institute on Aging; Nature; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurology; Neuronal Dysfunction; Neurons; Oxidants; Oxidative Stress; Pathology; Peripheral Nervous System Diseases; Pharmaceutical Chemistry; 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; Series; Serum; Source; 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; bench to bedside; cerebral atrophy; clinical development; course development; cytokine; design; drug candidate; drug development; entorhinal cortex; familial Alzheimer disease; glucagon-like peptide 1; in utero; in vivo; inhibitor/antagonist; interest; mouse model; nervous system disorder; neuroinflammation; neuron loss; neuropathology; neurotoxic; normal aging; novel; novel therapeutics; pomalidomide; pre-clinical; preclinical study; presenilin; presenilin-1; programs; protein aggregation; protein oligomer; proteostasis; resilience; response; small molecule; tau Proteins; treatment strategy

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 within the brain. Microarray studies indicate an overall rise in inflammatory and pro-oxidant genes with a decline in growth, anti-inflammatory and anti-oxidant genes in the brain of older versus adult rodents (Cribbs et al., J Neuroinflammation 9:179, 2012). In line with this, levels of brain pro-inflammatory cytokines have been found elevated with age in rodents and humans, and several regulatory molecules and anti-inflammatory cytokines reduced (Deleidi et al., Front Neurosci 9:172, 2015). As a source of these pro- and anti-inflammatory molecules, microglia are thereby implicated as the major culprit of this 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-alpha) is one of the primary pro-inflammatory cytokines synthesized and released by microglial cells. Once TNF-alpha is released, it may initiate a self-propagating cycle of unchecked inflammation (Frankola et al., CNS Neurol Disord Drug Targets 10:391-403, 2011). Pharmacological intervention to interrupt this cycle may be of significant benefit in the setting of neuroinflammation-mediated diseases. In 1993, Moreira et al., (J Exp Med 177:1675-80, 1993) described a series of studies showing that the drug thalidomide (THAL) was able to lower TNF-alpha protein levels post-transcriptionally by accelerating the degradation of its mRNA. Unfortunately, THAL is not a particularly potent TNF-alpha 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-alpha lowering activity has given rise to studies to differentiate these actions, understand THALs TNF-alpha structure/activity relationship and develop more potent analogs. In principle, the identification of analogs with enhanced anti- TNF-alpha activity and reduced teratogenic and neurotoxic effects may provide a viable treatment strategy for CNS neuroinflammatory and other forms of inflammatory disease. Our medicinal chemistry modifications to the backbone of THAL and newer analogs (namely pomalidomide (POM)) have generated an extensive library of novel agents (issued US patents owned: 7,973,057 and 8,927,725, and U.S. Patent Application No. 62/235,105). Our focus is to identify well-tolerated drug-like compounds with more potent anti- TNF-alpha 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 and Focused Aims: AD is a complex disorder that manifests as progressive dementia with few other symptoms. With a long meandering course, the disease is associated with deposits of amyloid-beta protein (ABeta) of 40 and 42 amino acids as much as 20 years prior to the 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 ABeta, and brain atrophy follows after five further years. However, the resilience and redundancy of the nervous system protects the affected subject from dementia for around five further years after the detection of atrophy by brain image analysis. The discovery that familial AD (FAD) mutations in ABeta precursor protein (APP) and presenilins (PSEN1) and 2 (PSEN2) increase ABeta42, 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 ABeta deposition further boosts the amyloid hypothesis. Despite the consistency of this finding, the time-dependent ABeta-triggered mechanisms of neuronal dysfunction and degeneration remain unclear; thereby making therapeutic intervention difficult. As ABeta oligomers and aggregates are tolerated over an extended time, their toxicity may not be the direct cause of neurodegeneration but, rather, the initiator of a cascade of events that become self-propagating and then drive disease 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 ABeta and MAPT can induce microglia activation (McGeer & 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-alpha 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-alpha levels correlates with disease progression (Tarkowski et al., J Neurol Neurosurg Psychiatry 74:1200-5, 2003). Paralleling this, elevated expression of TNF-alpha is reported within the entorhinal cortex of 3xTg-AD mice prior to the appearance of amyloid and tau pathology, and this increase associates with the onset of cognitive deficits in these mice and later neuronal loss (Janelsins et al. J Neuroinflamm 2:23, 2005). We hypothesize that failure of protein homeostasis leads to accumulation of proteins (e.g., ABeta, APOE and MAPT) that induce microglial activation and a proinflammatory M1 response to instigate their removal. The continuing generation of protein (ABeta, APOE and MAPT) leads to maintenance of a chronic M1 response, an impairment of transition to an anti-inflammatory M2 response (particularly in the aging brain that is already vulnerable to inflammation) with ensuing neuronal impairment observed in the animal models and in preclinical AD that eventually leads to cell death. Proinflammatory cytokines, like TNF-alpha, induce vascular changes to allow lymphocyte infiltration that may underpin reported cerebral vasculature leakiness of AD patients and related Tg mouse models. Moreover, TNF-alpha induces ABeta production in cellular and animal AD models, further increasing its accumulation and the entire cascade. Our focus is understanding 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-alpha generation as well as with the new more potent small molecule TNF-alpha synthesis inhibitors synthesized and patented for NIH by our research collaborative group within the Intramural Research Program of NIA.

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，尤其是在大脑内。 微阵列研究表明，炎症和促氧化剂基因的总体上升，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 Neuroinflammation 9：179，2012）。与此一致，发现脑炎性细胞因子的水平随啮齿动物和人类的年龄而升高，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）。作为这些促炎和抗炎分子的来源，小胶质细胞被视为这种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-Alpha）是小胶质细胞合成并释放的主要促炎细胞因子之一。一旦释放了TNF-Alpha，它可能会引发不受组织的炎症的自传播周期（Frankola等人，CNS Neurol疾病药物靶标目标10：391-403，2011）。在神经炎症介导的疾病的情况下，中断此周期的药理干预可能具有重大益处。 1993年，Moreira等人（J Exp Med 177：1675-80，1993）描述了一系列研究表明，在其后通过加速其mRNA的降解，可以在转录后降低TNF-Alpha蛋白水平。不幸的是，Thal并不是一种特别有效的TNF-Alpha降低剂，并且与临床剂量的子宫内胚胎，镇静和周围神经病的严重伤亡不良影响有关（Calabrese＆Fleischer，Am J Med Med，J Med Med 108：487-95-95-95-95，2000; DeCourt et al al al al al al al al al al al al al al al al al al al al al al al al curr al as court al as court al as curr al as as curr al as as ac al as cur al as as as al as al as al as al al as as a al as as as al as as as as as as as as as as 2014年3月14日。然而，对THAL TNF-Alpha降低活性的观察已经引起了研究，以区分这些动作，了解Thals TNF-Alpha结构/活性关系并发展出更有效的类似物。原则上，鉴定具有增强抗TNF-α活性的类似物以及致病性和神经毒性作用降低可能为中枢神经系统神经炎症性和其他形式的炎症性疾病提供可行的治疗策略。我们对Thal和更新类似物（即Pomalidomide（POM））的骨干的药物化学修改已产生了广泛的新型代理商（已发行美国专利：7,973,057和8,927,725，以及8,927,725，以及美国专利的62/2355,105）。我们的重点是从我们产生的文库中鉴定出具有更有效的抗TNF-Alpha活性，并将其作为实验药物发展为实验药物，以表征神经炎性成分在AD和相关疾病中的作用。 问题和集中目的：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。随着漫长的曲折病程，该疾病与淀粉样蛋白（ABETA）的沉积物有关，为40和42氨基酸的沉积物在痴呆症的发展前约20年。它还诱导微管相关蛋白Tau（MAPT）作为神经原纤维缠结（NFTS）的细胞内积累，与痴呆症的程度更加紧密相关（Sambamurti等人，Curr Alzheimer res 3：81-90，2006; Baranello et al al al al al alzheimer res al al al alzheimer res as al al al al al al al al al al alzhemerer res。 NFT发生在Abeta之后约10年，脑萎缩又在五年后随后发生。然而，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，大约五年来通过大脑图像分析发现萎缩。 ABETA前体蛋白（APP）和Presenilins（PSEN1）和2（PSEN2）增加Abeta42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种群中检测到的载脂蛋白E（APOE）的E4变体的发现，也促进了Abeta沉积进一步增强了淀粉样假说。尽管这一发现具有一致性，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Abeta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退行性的直接原因，而是一系列级联事件的发​​起者，这些事件成为自我传播，然后驱动疾病进展。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ABETA和MAPT的存在可以诱导小胶质细胞激活（McGeer＆McGeer，Acta Neuropathol 126：479-97，2013），并且在AD脑中神经炎症的直接证据已被Vivo In In In In vivo Pet Imaging（Schuitemaker Imaging）显示（Schuitemaker Imaging（Schuitemaker）（Schuitemaker et al。值得注意的是，AD患者的血清和CSF中促炎性细胞因子的水平升高，TNF-Alpha的水平升高了多达25倍（Tarkowski等，J Clin Immunol 19：223-30，1999）。在发展为AD的MCI受试者中，CSF TNF-Alpha水平的上升与疾病进展相关（Tarkowski等人，J Neurol Neurol Neurosurg Psychiatry 74：1200-5，2003）。在淀粉样蛋白和Tau病理学出现之前，在3xTG-AD小鼠的内hin骨皮层中报道了TNF-Alpha表达的升高，并且这种增加与这些小鼠和后来的神经元损失的认知缺陷发作有关（Janelsins等人（Janelsins等）（Janelsins等。 我们假设蛋白质稳态失败会导致蛋白质（例如Abeta，ApoE和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（ABETA，APOE和MAPT）导致维持慢性M1反应，从而损害向抗炎的M2反应过渡（尤其是在已经容易发生炎症的衰老大脑中，并且在动物模型中观察到的随之而来的神经元障碍，并在动物模型中观察到的神经元障碍，并最终导致细胞死亡。促炎细胞因子（如TNF-α）会诱导血管变化，从而使淋巴细胞浸润，可能支撑了AD患者的脑血管泄漏和相关TG小鼠模型。此外，TNF-Alpha在细胞和动物AD模型中诱导Abeta产生，进一步增加了其积累和整个级联。我们的重点是了解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，这些模型可能反映出疾病病理学的时间比目前可用的病理更多。我们还通过临床认可的免疫调节剂POM评估了这些缺陷的处理，该药物POM降低了TNF-Alpha的产生以及新的更有效的小分子TNF-Alpha合成抑制剂合成和NIH的NIH专利，由我们的NIA内部研究计划中的NIH综合。