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：
10210993
负责人：
Allen Bernard Reitz
金额：
$ 141.28万
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/10210993
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 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 Diagnosis clinical development cytotoxicity disorder subtype epidemiologic data fluorodeoxyglucose positron emission tomography human model imaging study in vivo induced pluripotent stem cell inhibitor/antagonist 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是基于大量流行病学的阿尔茨海默氏病（AD），AD-TDP中的混合蛋白质。与TDP-43的包含物与AD患者认知能力下降相关的数据。 TDP-43相关广告已经被称为与年龄相关的TDP-43脑病（晚）以及其他首字母缩写词，在AD（AD-TDP）中，TDP-43的新认识的重要性是基本的。广告是最常见的原因后期到后期的认知障碍和痴呆症，全世界约有3000万人以对临床和病理研究的广泛综述，TDP-43蛋白质病与敏感性有关老年人发生的痴呆综合征。对归因风险的统计分析表明TDP-43 相关广告是一个主要的公共卫生问题，占临床诊断广告病例的20％失智。该TDP-43蛋白质病是与其他TDP-43的独特临床和病理实体也可能使用TDP-43靶向疗法治疗的相关疾病，例如肌萎缩症硬化症（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识别基于TDP-43的治疗剂来治疗其他 TDP-43起着主要且统一的作用的疾病。我们发现了与 TDP-43以抑制RNA与TDP-43的结合并防止TDP-43聚集的方式，并具有活性在三个模型中提出了治疗作用：（1）在果蝇（2）C9orf72患者衍生的IPSC的诱导运动神经元（IMN）和（3）表达的小鼠人类TDP-43（THY1启动子）。来自二维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RRM2结合，其中包含其中一个与RRM1一起参与关键且功能相关的盐桥的氨基酸。最近的宠物成像研究描述了根据FDG的比例，描述了可能选择AD-TDP患者进行临床试验的代谢标记在大脑的不同区域进行成像。在这个项目中，我们试图发现，验证和开发新的小型核酸与TDP-43和TDP-43聚集抑制剂的分子抑制剂以治疗AD-TDP。目的 1是新型TDP-43配体的体外效能和类似药物样特性的优化，包括穿透进入大脑，并使用全面的药品进行的半衰期和安全措施行业标准测定和标准。 AIM 2涉及使用HTDP-43翻译的目标参与研究 HEK293T细胞，患者衍生的IPSC诱导运动神经元，动态光散射分析结合TDP-43的配体的聚集和X射线晶体学。 AIM 3是在动物模型中评估的 TDP-43病理学，最初使用THY1启动子，然后是基于HTDP-43的鼠标模型在没有运动定义的情况下证明了认知障碍。 AIM 4包括辅助研究，扩大合成，多种物种PK和啮齿动物毒性。