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Therapeutics targeting TDP-43 to treat Alzheimer's disease and related disorders

针对 TDP-43 治疗阿尔茨海默病及相关疾病的疗法

基本信息

批准号：
10662334
负责人：
Allen Bernard Reitz
金额：
$ 136.5万
依托单位：
FOX CHASE CHEMICAL DIVERSITY CENTER, INC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662334
关键词：
Accounting Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amino Acids Amyotrophic Lateral Sclerosis Animal Model Binding Binding Proteins Biological Assay Biological Models Brain Brain region C-terminal C9ORF72 Canis familiaris Cell Line Cells Clinical Clinical Trials Crystallography Cytochrome P450 DNA-Binding Proteins Data Correlations Dementia Development Disease Docking Dose Drosophila genus Drug Industry Elderly Encephalopathies Evaluation Frontotemporal Lobar Degenerations Genetic Transcription Glycine Half-Life Human Image Impaired cognition In Vitro Industry Standard Libraries Ligand Binding Ligands Liver Microsomes Mammalian Cell Measures Metabolic Metabolic Marker Modeling Motor Neurons Mus Nucleic Acid Binding Pathologic Pathology Patients Penetration Permeability Persons Pharmaceutical Preparations Phase Plasma Plasma Proteins Play Polymorph Positron-Emission Tomography Property Proteins Public Health RNA Binding RRM1 gene RRM2 gene Rattus Regulator Genes Ribonucleotides Risk Rodent Roentgen Rays Role Safety Sodium Chloride Solubility Spliced Genes Statistical Data Interpretation Syndrome TDP-43 aggregation Testing Therapeutic Therapeutic Effect Toxic effect Toxicity Tests Toxicology Transfection X-Ray Crystallography acronyms age related aqueous clinical development clinical diagnosis cytotoxicity disorder subtype epidemiologic data fluorodeoxyglucose positron emission tomography human model imaging study improved in vivo induced pluripotent stem cell inhibitor light scattering limbic-predominant age-related TDP-43 encephalopathy locomotor deficit mouse model mutant new chemical entity novel nucleic acid binding protein nucleic acid inhibitor preclinical development prevent prion-like promoter protein TDP-43 protein function response scale up small molecule small molecule inhibitor stability testing targeted treatment therapeutic target

项目摘要

TDP-43 is a mixed proteinopapthy in Alzheimer’s disease (AD), AD-TDP, based on substantial epidemiological data correlating TDP-43 inclusions with cognitive decline in AD patients. TDP-43 associated AD has been termed as limbic-predominant age-related TDP-43 encephalopathy (LATE) as well as other acronyms, underlying the newly-recognized importance of TDP-43 in AD (AD-TDP). AD is the most common cause of mid- to late-life cognitive impairment and dementia, afflicting ~30 million people worldwide Based on an extensive review of clinical and pathological studies, TDP-43 proteinopathy is associated with an amnestic dementia syndrome that occurs in older adults. A statistical analysis of attributable risk suggests that TDP-43 associated AD is a major public health issue accounting for up to 20% of cases of clinically diagnosed AD dementia. This TDP-43 proteinopathy is a distinct clinical and pathological entity from other TDP-43 associated diseases that may also be treatable with a TDP-43 targeted therapy, such as amyotrophic lateral sclerosis (ALS) and certain forms of frontotemporal lobar degeneration (FTLD-TDP). Therefore, successful completion of this project has the potential to identify TDP-43-based therapeutics for the treatment of other diseases where TDP-43 plays a major and causative role. We have discovered small molecules that bind to TDP-43 in such a way as to inhibit binding of RNA to TDP-43 and prevent TDP-43 aggregation, with activity suggestive of a therapeutic effect in three models: (1) human wild-type and mutant TDP-43 expressed in Drosophila, (2) induced motor neurons (iMNs) from C9orf72 patient-derived iPSCs, and (3) mice expressing human TDP-43 (Thy1 promotor). Evidence from 2-D NMR studies and computational docking analysis suggests that these inhibitors are binding to ribonucleotide recognition motif RRM2 which contains one of the amino acids involved in a critical and functionally-relevant salt bridge with RRM1. A recent PET imaging study describes a metabolic marker to potentially select AD-TDP patients for clinical trials based on ratios of FDG imaging in different regions of the brain. In this project we seek to discover, validate and develop new small- molecule inhibitors of nucleic acid binding to TDP-43 and TDP-43 aggregation inhibitors to treat AD-TDP. Aim 1 is the optimization of in vitro potency and drug-like properties of novel TDP-43 ligands including penetration into the brain and acceptable half-life and safety measures using a comprehensive battery of pharmaceutical industry-standard assays and criteria. Aim 2 involves target engagement studies using hTDP-43 transfected in HEK293T cells, patient-derived induced motor neurons from iPSCs, dynamic light scattering analysis of aggregation, and X-ray crystallography of ligands bound into TDP-43. Aim 3 is evaluation in animal models of TDP-43 pathology, initially using a Thy1 promoter followed by a hTDP-43 based mouse model that demonstrates cognitive impairment in the absence of locomotor deficits. Aim 4 includes IND-enabling studies, scale-up synthesis, multi-species PK and rodent toxicity.

TDP-43是阿尔茨海默病（AD）中的一种混合蛋白病，AD-TDP，基于大量流行病学研究， AD患者中TDP-43内含物与认知下降相关的数据。TDP-43相关AD已被被称为边缘优势年龄相关TDP-43脑病（LATE）以及其它首字母缩写，这是TDP-43在AD（AD-TDP）中新认识到的重要性的基础。AD是最常见的原因中晚期认知障碍和痴呆症，困扰着全球约3000万人。广泛回顾临床和病理学研究，TDP-43蛋白质病与遗忘有关，老年痴呆综合症。归因风险的统计分析表明，TDP-43 相关AD是一个主要的公共卫生问题，占临床诊断AD病例的20 痴呆这种TDP-43蛋白病是一种不同于其他TDP-43蛋白病的临床和病理实体也可以用TDP-43靶向治疗治疗的相关疾病，如肌萎缩侧索硬化症，硬化症（ALS）和某些形式的额颞叶变性（FTLD-TDP）。因此，成功该项目的完成有可能确定基于TDP-43的治疗方法，用于治疗其他 TDP-43起主要和致病作用的疾病。我们发现了一些小分子，以抑制RNA与TDP-43结合并防止TDP-43聚集的方式，具有活性提示在三种模型中的治疗效果：（1）人野生型和突变型TDP-43，其表达于果蝇，（2）来自C9 orf 72患者来源的iPSC的诱导运动神经元（iMN），和（3）表达C9 orf 72的小鼠。人TDP-43（Thy 1启动子）。来自2-D NMR研究和计算对接分析的证据表明这些抑制剂与核糖核苷酸识别基序RRM 2结合，该基序含有一种参与与RRM 1的关键和功能相关的盐桥的氨基酸。最近的PET成像研究描述了一种代谢标志物，可根据FDG比率选择AD-TDP患者进行临床试验在大脑的不同区域成像。在这个项目中，我们寻求发现，验证和开发新的小- 与TDP-43结合的核酸分子抑制剂和TDP-43聚集抑制剂以治疗AD-TDP。目的 1是新型TDP-43配体的体外效力和药物样性质的优化，包括渗透以及可接受的半衰期和安全性措施，使用一套全面的药物组合，行业标准分析和标准。目的2涉及使用转染的hTDP-43的靶接合研究。 HEK 293 T细胞，来自iPSC的患者来源的诱导运动神经元，动态光散射分析聚集和结合到TDP-43中的配体的X射线晶体学。目的3是在动物模型中进行评价， TDP-43病理学，最初使用Thy 1启动子，随后使用基于hTDP-43的小鼠模型，在没有运动缺陷的情况下表现出认知障碍。目标4包括国家自主研发能力研究，放大合成、多物种PK和啮齿动物毒性。