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

描述(由申请人提供)：由于老龄化人口的人口结构变化，阿尔茨海默病(AD)的流行率在全球范围内不断上升，因此对治疗阿尔茨海默病(AD)的疾病修饰药物的需求非常大，而且增长迅速。AD是美国第三大最昂贵的疾病，每年直接损失超过2000亿美元。拟议的IIB阶段计划是为了继续开发小分子药物，特别是在第二阶段计划中发现的tau单体自我结合成低聚物的最早步骤中抑制tau聚集。Tau寡聚体在神经元中积累的减少也应该会抑制更高级别聚集体的形成。这些药物也可能有效地减少细胞外tau寡聚体，这些寡聚体不是不可逆转的联系。细胞外区tau寡聚体的减少有望消除记忆形成的关联性损害，并将病理传播到健康的邻近神经元。因此，预计减少细胞外tau寡聚体的治疗干预应该既能改善记忆，又能减缓或阻止AD患者的疾病进展。在临床前和临床研究中，记忆力的症状性改善可以作为药物疗效的早期指标。在项目的第二阶段，该分析被转换为高通量的化合物筛选平台，进行验证，并用于筛选不同的化合物文库。选择并克隆了tau寡聚体的抗体片段(Tian等人。2012年)。拟议的IIB阶段计划的具体目标是：“在细胞分析中进行二次筛选，以抑制tau寡聚体的积累；提高在一次和二次分析中选择的化合物的效力；在记忆形成的急性小鼠模型中验证tau寡聚体的靶点；在急性小鼠模型中选择化合物，用于在慢性tau病模型中进行测试”制定调控策略拟议的IIB阶段计划的预期结果是选择至少三种或更多针对tau寡聚体的先导候选化合物，用于在AD和tauathy动物模型中进行评估。为了实现这一结果，将使用tau寡聚体形成的细胞模型和药物化学的二次筛选来优化和选择化合物，以便在tau诱导的记忆功能障碍的急性小鼠模型中进行测试。在验证了tau齐聚物靶标的模型后，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。在拟议的计划结束时，将编写一份详细的监管战略，以指导临床前直到IND提交和Ph1临床试验。关键词：阿尔茨海默病，肌萎缩侧索硬化症，神经退行性疾病，药物发现，tau，寡聚体，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