Drug Discovery against the Early, Secreted and Toxic Tau in Alzheimer's Disease

针对阿尔茨海默病早期、分泌性和毒性 Tau 蛋白的药物发现

• 批准号: 9050609
• 负责人: Kun Ping Lu
• 金额: $ 35.67万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050609
• 关键词: 19p13.2; Active Immunization; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Apoptosis; Attention; Biological Markers; Brain; Cell model; Chemistry; Cognitive deficits; Development; Disease; Down-Regulation; Epitopes; Event; Health; Human; Hybridomas; Immunization; Immunotherapy; In Vitro; Injury; Isomerism; Late Onset Alzheimer Disease; Lead; Left; Life; Memory Loss; Memory impairment; Microtubules; Molecular Conformation; Monoclonal Antibodies; Mus; Mutation; Neurites; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Onset of illness; Outcome; Passive Immunization; Pathology; Patients; Peptides; Peptidylprolyl Isomerase; Phosphopeptides; Prevalence; Protein Dephosphorylation; Research; Resistance; Staging; Stress; Tauopathies; Testing; Therapeutic; Time; Toxic effect; Traumatic Brain Injury; Vaccines; design; drug discovery; effective therapy; efficacy trial; improved; in vivo; innovation; mouse model; neurofibrillary tangle formation; neuron loss; neuropathology; neurotoxicity; neutralizing antibody; neutralizing monoclonal antibodies; neutralizing vaccine; new technology; novel; overexpression; peptide A; plaque lesion; polyclonal antibody; prevent; protein misfolding; tau Proteins; tau aggregation; tau-1; therapy development; trial design

DESCRIPTION (provided by applicant): Prevalence of Alzheimer's disease (AD) may quadruple worldwide by 2050, but there is no effective treatment available. The AD hallmark lesions are plaques made of A� peptides and tangles of phosphorylated tau (p-tau). [A� immunization has effectively eliminated its target in brains even in AD patients, albeit questions remain about its efficacy and trial design. Tauopathy correlates well with memory decline in AD and also is a defining feature of other tauopathies. Moreover, active or passive immunization against p-tau tangle epitopes or tau seeding shows promising efficacy in mouse models. However, since neuronal dysfunction long precedes tangle formation, immunotherapies specifically against the early pathogenic pretangle events that lead to memory loss in AD are being actively pursued.] Notably, an early event in AD tauopathy is tau hyperphosphorylation especially on Ser/Thr-Pro motifs. We have previously found that the phosphorylated Thr231-Pro motif in tau (pT231-tau) exists in the cis and trans conformations, and also identified the unique prolyl isomerase Pin1 to accelerate their conversion to prevent p-tau misfolded and inhibit tauopathy. Furthermore, Pin1 is inhibited by multiple mechanisms in human MCI and AD neurons, whereas the Pin1 SNP that prevents its down-regulation is associated with delayed AD onset. In addition, human Pin1 is located at 19p13.2 associated with late-onset AD pT231-tau is at the beginning of sequential p-tau epitopes in AD pretangle neurons and pT231-tau in CSF correlates with memory loss and tracks MCI conversion to AD. These results suggest that pT231-tau is a very early disease-initiating event in AD. [We have recently developed a novel technology to generate the first cis and trans pT231-tau polyclonal antibodies, and identified the previously unrecognized early pathogenic cis tau that leads to tauopathy in MCI and AD. We now created neutralizing mAb that effectively removed this early, secreted and toxic cis tau in vitro, ex vivo and in mice. Thus, this proposal is designed to test our novel hypothesis that neutralizing conformation-specific mAbs and vaccines against only the early, secreted and toxic cis p-tau while leaving the healthy trans untouched may be highly efficacious and specific in halting or even preventing tauopathy in AD. Aim 1 will further identify the best cis and trans mAbs and evaluate their efficacy and mechanisms in neutralizing the ability of p-tau to induce and spread neurotoxicity in vitro and ex vivo. Aim 2 will evaluate the effects of cis and trans pT231-tau mAbs on tauopathy in two different but complementary mouse models of tauopathy. Aim 3 will develop and evaluate the effects of cis and trans pT231-tau vaccines on tauopathy in two mouse models of tauopathy. The expected outcomes would constitute innovative conformation-specific immunotherapies against the very early, secreted and toxic cis pT231-tau in tauopathy, raising the unique opportunity of halting or preventing tauopathy and memory loss in AD patients at early stages. This research can offer a unique approach for therapeutics directed specifically against the early pathogenic misfolded proteins in AD.]

描述（由申请人提供）：到2050年，阿尔茨海默病（AD）的患病率可能会在全球范围内翻两番，但没有有效的治疗方法。AD标志性病变是由A肽和磷酸化tau（p-tau）缠结组成的斑块。免疫接种有效地消除了其在大脑中的目标，即使在AD患者中，尽管其疗效和试验设计仍存在问题。tau蛋白病与AD的记忆力下降密切相关，也是其他tau蛋白病的定义特征。此外，针对p-tau缠结表位或tau接种的主动或被动免疫在小鼠模型中显示出有希望的功效。然而，由于神经元功能障碍早在缠结形成之前，因此正在积极寻求特异性针对导致AD记忆丧失的早期致病性预缠结事件的免疫疗法。值得注意的是，AD tau蛋白病的早期事件是tau蛋白过度磷酸化，特别是在Ser/Thr-Pro基序上。我们以前发现tau蛋白中磷酸化的Thr 231-Pro基序（pT 231-tau）以顺式和反式构象存在，并且还鉴定了独特的脯氨酰异构酶Pin 1，以加速它们的转化，从而防止p-tau错误折叠并抑制tau蛋白病。此外，Pin 1在人类MCI和AD神经元中受到多种机制的抑制，而阻止其下调的Pin 1 SNP与延迟的AD发作相关。此外，人Pin 1位于与晚发型AD相关的19p13.2，pT 231-tau位于AD前缠结神经元中连续p-tau表位的开始，CSF中的pT 231-tau与记忆丧失相关，并跟踪MCI向AD的转化。这些结果表明，pT 231-tau是AD中非常早期的疾病起始事件。[We最近开发了一种新的技术来产生第一个顺式和反式pT 231-tau多克隆抗体，并鉴定了以前未被认识的导致MCI和AD中tau病变的早期致病性顺式tau。我们现在创建了中和mAb，其在体外、离体和小鼠中有效地去除这种早期分泌的和毒性的顺式tau。因此，该提议旨在测试我们的新假设，即仅针对早期、分泌的和毒性的顺式p-tau的中和构象特异性mAb和疫苗，同时保持健康的反式不变，可能在停止或甚至预防AD中的tau病变方面是高度有效和特异的。目的1将进一步鉴定最佳的顺式和反式mAb，并评估它们在体外和离体中和p-tau诱导和扩散神经毒性的能力的功效和机制。目的2将在两种不同但互补的tau蛋白病小鼠模型中评价顺式和反式pT 231-tau mAb对tau蛋白病的作用。目的3在两种小鼠tau蛋白病模型中开发和评价顺式和反式pT 231-tau疫苗对tau蛋白病的作用。预期的结果将构成针对tau蛋白病中非常早期的、分泌的和毒性的顺式pT 231-tau的创新构象特异性免疫疗法，提高了在早期阶段停止或预防AD患者中的tau蛋白病和记忆丧失的独特机会。这项研究可以为专门针对AD中早期致病性错误折叠蛋白的治疗提供独特的方法。