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: 8759345
• 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/8759345
• 关键词: 19p13.2; Active Immunization; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Apoptosis; Attention; Biological Markers; Brain; Cell model; Chemistry; Clinical Trials Design; 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; 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; plaque lesion; polyclonal antibody; prevent; protein misfolding; tau Proteins; tau aggregation; tau-1; therapy development

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 Aβ peptides and tangles of phosphorylated tau (p-tau). [Aβ 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，全球阿尔茨海默病 (AD) 的患病率可能会翻两番，但目前尚无有效的治疗方法。 AD 标志性病变是由 Aβ 肽和磷酸化 tau (p-tau) 缠结组成的斑块。 [Aβ 免疫即使在 AD 患者中也能有效地消除其大脑中的目标，尽管对其功效和试验设计仍然存在疑问。 tau 蛋白病与 AD 中的记忆力下降密切相关，也是其他 tau 蛋白病的一个明显特征。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于缠结形成，因此正在积极寻求专门针对导致 AD 中记忆丧失的早期致病性前缠结事件的免疫疗法。]值得注意的是，AD tau 病的早期事件是 tau 过度磷酸化，尤其是 Ser/Thr-Pro 基序上的 tau 过度磷酸化。我们之前发现tau中磷酸化的Thr231-Pro基序（pT231-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Pin1来加速其转化，以防止p-tau错误折叠并抑制tau病。此外，Pin1 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 Pin1 SNP 与 AD 延迟发作有关。此外，人类 Pin1 位于与迟发性 AD 相关的 19p13.2，pT231-tau 位于 AD 前缠结神经元中连续 p-tau 表位的开头，CSF 中的 pT231-tau 与记忆丧​​失相关并追踪 MCI 向 AD 的转化。这些结果表明 pT231-tau 是 AD 中非常早期的疾病起始事件。 [我们最近开发了一种新技术来生成第一个顺式和反式 pT231-tau 多克隆抗体，并鉴定了以前未被识别的早期致病性顺式 tau，它导致 MCI 和 AD 中的 tau 病。我们现在创建了中和单克隆抗体，可以在体外、离体和小鼠体内有效去除这种早期分泌的有毒顺式 tau 蛋白。因此，该提案旨在检验我们的新假设，即中和构象特异性单克隆抗体和疫苗仅针对早期、分泌性和有毒的顺式 p-tau，同时保持健康的反式不受影响，可能对于阻止甚至预防 AD 中的 tau 病非常有效和特异。目标 1 将进一步确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 诱导和传播神经毒性的能力方面的功效和机制。目标 2 将在两种不同但互补的 tau 蛋白病小鼠模型中评估顺式和反式 pT231-tau mAb 对 tau 蛋白病的影响。目标 3 将开发并评估顺式和反式 pT231-tau 疫苗对两种 tau 蛋白病小鼠模型的 tau 蛋白病的影响。预期结果将构成针对 tau 蛋白病中非常早期、分泌性和有毒的顺式 pT231-tau 的创新构象特异性免疫疗法，为早期阻止或预防 AD 患者的 tau 蛋白病和记忆丧失提供独特的机会。这项研究可以提供一种独特的治疗方法，专门针对 AD 中的早期致病性错误折叠蛋白。]