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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：
10436955
负责人：
Allen Bernard Reitz
金额：
$ 138.6万
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/10436955
关键词：
Accounting Alzheimer&apos s Disease Alzheimer&apos s disease patient 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 Chemicals Clinical Clinical Trials Crystallography Cytochrome P450 DNA-Binding Proteins Dementia Development Disease Docking Dose Drosophila genus Drug Industry Elderly Evaluation Evaluation Studies Frontotemporal Lobar Degenerations Genetic Transcription Glycine Half-Life Human Image Impaired cognition In Vitro Industry Standard Libraries 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 Transition 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 Suggestion Syndrome TDP-43 aggregation Testing Therapeutic Therapeutic Effect Toxic effect Toxicity Tests Toxicology X-Ray Crystallography acronyms aqueous base clinical development clinical diagnosis cytotoxicity disorder subtype epidemiologic data fluorodeoxyglucose positron emission tomography human model imaging study in vivo induced pluripotent stem cell inhibitor light scattering limbic-predominant age-related TDP-43 encephalopathy locomotor deficit mouse model mutant 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)的一种混合性蛋白病变，AD-TDP，基于大量的流行病学阿尔茨海默病患者TDP-43包涵体与认知功能下降的相关数据。与TDP-43相关的AD已经被称为边缘占优势的年龄相关的TDP-43脑病(LATE)以及其他缩写，新认识的TDP-43在AD(AD-TDP)中的重要性。广告是最常见的原因中老年认知障碍和痴呆症，困扰着全球约3000万人广泛的临床和病理研究回顾，TDP-43蛋白病与遗忘症相关发生在老年人身上的痴呆综合症。对归因风险的统计分析表明，TDP-43 相关性AD是一个主要的公共卫生问题，占临床诊断的AD病例的20% 痴呆症。这种TDP-43蛋白病是一种不同于其他TDP-43的临床和病理实体相关疾病，也可以用TDP-43靶向治疗，如肌萎缩侧索硬化硬化症(ALS)和某些形式的额颞叶变性(FTLD-TDP)。因此，成功了该项目的完成有可能确定基于TDP-43的治疗其他疾病的疗法 TDP-43起主要致病作用的疾病。我们发现了结合在一起的小分子 TDP-43，抑制RNA与TDP-43的结合并阻止TDP-43聚集，具有活性提示在三个模型中的治疗效果：(1)人野生型和突变型TDP-43在果蝇，(2)从C9orf72患者来源的IPSCs诱导运动神经元(IMN)，以及(3)小鼠表达人TDP-43(Thy1启动子)。来自二维核磁共振研究和计算对接分析的证据提示这些抑制物与核糖核苷酸识别基序RRM2结合，RRM2包含与RRM1有关的关键和功能相关盐桥的氨基酸。最近的一项PET成像研究描述了一种基于FDG比率潜在地选择AD-TDP患者进行临床试验的代谢标志物在大脑的不同区域进行成像。在这个项目中，我们寻求发现、验证和开发新的小型与TDP-43结合的核酸分子抑制剂和TDP-43聚集抑制剂治疗AD-TDP。目标一是新型TDP-43配体的体外效力和类药物性质的优化，包括渗透性进入大脑和可接受的半衰期和安全措施使用全面的药物电池符合行业标准的分析方法和标准。AIM 2包括使用hTDP-43转染的靶向结合研究 HEK293T细胞，患者来源的IPSCs诱导的运动神经元，动态光散射分析结合在TDP-43上的配体的聚集和X-射线结晶学。目的3是在动物模型中评价 TDP-43病理，最初使用Thy1启动子，然后是基于hTDP-43的小鼠模型在没有运动障碍的情况下表现出认知障碍。目标4包括支持IND的研究，放大合成、多物种PK和啮齿动物毒性。