High throughput tau oligomer drug screening assay for Alzheimer's disease

描述（由申请人提供）：由于人口老龄化的人口结构变化，阿尔茨海默病（AD）的患病率在全球范围内不断增加，因此对疾病改善药物的需求非常大且快速增长。阿尔茨海默病是美国第三大最昂贵的疾病，每年的直接成本超过2000亿美元。拟议的IIB期项目是继续开发小分子药物，在II期项目中发现的tau单体自结合成低聚物的早期阶段特异性抑制tau聚集。神经元中tau寡聚物积累的减少也会抑制高阶聚集体的形成。这些药物也可能有效地减少细胞外tau低聚物，而这些低聚物不是不可逆的。细胞外隔室中tau寡聚物的减少有望消除记忆形成的关联损伤和病理向健康邻近神经元的传播。因此，预期减少细胞外tau寡聚物的治疗干预将导致AD患者记忆的改善和疾病进展的减缓或阻止。在临床前和临床研究中，记忆的症状改善可作为药物疗效的早期指标。在该项目的第二阶段，该分析被转化为高通量化合物筛选平台，经过验证，并用于筛选多种化合物库。选择并克隆了tau寡聚物的抗体片段（Tian et al. 2012）。建议的第ii期计划具体目标是：“执行二级屏幕抑制τ低聚物积累在细胞化验”提高选择的力量化合物在中小学化验“验证τ低聚物的目标在记忆形成的急性小鼠模型”中选择化合物急性慢性tauopathy模型中小鼠模型进行测试”制定管理策略的预期结果IIB阶段提出了程序的选择至少三个或更多领先候选人目标化合物τ寡聚物在AD和牛头病动物模型中的评价。为了获得这一结果，将在tau低聚物形成和药物化学的细胞模型中进行二次筛选，以优化和选择化合物，用于tau诱导的急性小鼠记忆功能障碍模型的测试。在验证tau低聚物靶点模型后，将筛选选定的活性化合物并选择候选化合物进行进一步开发。在拟议的项目结束时，将编写详细的监管策略，以指导临床前到IND提交和Ph 1临床试验。关键词：阿尔茨海默病，tau病变，神经退行性疾病，药物发现，tau，寡聚物，细胞模型，小鼠模型，记忆

DESCRIPTION (provided by applicant): There is a very large and rapidly growing unmet need for disease-modifying drugs for Alzheimer's disease (AD) as its prevalence is increasing worldwide due to demographic shifts in the aging population. AD is the third most costly disease in the US with direct costs over $200 billion annually. The proposed phase IIB program is for the continued development of small molecule drugs specifically inhibiting tau aggregation at the earliest steps of tau monomer self-association into oligomers that were discovered during the phase II program. A decrease in tau oligomer accumulation in neurons should also inhibit the formation of higher order aggregates. These drugs may also be effective in reducing extracellular tau oligomers that are not irreversibly linked. A decrease of tau oligomers in the extracellular compartment holds promise to eliminate the associative impairment of memory formation and the propagation of pathology to healthy neighboring neurons. Therefore, it is anticipated that therapeutic intervention that diminishes extracellular tau oligomers should lead to both an improvement in memory and a slowing or arresting of disease progression in AD patients. Symptomatic improvement in memory may be used as an early indication of drug efficacy in preclinical and clinical studies. In Phase II of the project, the assay was converted t a high throughput compound-screening platform, validated, and used to screen a diverse compound library. Antibody fragments for tau oligomers were selected and cloned (Tian et al. 2012). The proposed phase IIB program Specific Aims are: " Perform secondary screen in cell assays for inhibition of tau oligomer accumulation " Improve the potency of selected compounds in the primary and secondary assays " Validate the tau oligomer target in an acute mouse model of memory formation " Select compounds in the acute mouse model for testing in a chronic tauopathy model " Develop regulatory strategy The anticipated outcome of the proposed Phase IIB program is the selection of at least three or more lead candidate compounds targeting tau oligomers for evaluation in animal models of AD and tauopathies. To attain this result, secondary screening in cell models of tau oligomer formation and medicinal chemistry will be used to optimize and select compounds for testing in the acute mouse model of tau-induced memory dysfunction. Following validation of the model for the tau oligomer target, selected active compounds will be screened and candidates chosen for further development. At the conclusion of the proposed program, a detailed regulatory strategy will be written to guide preclinical up to the IND submission and Ph 1 clinical trials. Key Words: Alzheimer's disease, tauopathy, neurodegenerative disease, drug discovery, tau, oligomer, cell model, mouse model, memory