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：
10621622
负责人：
Allen Bernard Reitz
金额：
$ 40.94万
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/10621622
关键词：
4-Aminopyridine Accounting Address Alzheimer&apos s Disease Alzheimer&apos s disease patient Amino Acids Amygdaloid structure Amyotrophic Lateral Sclerosis Animal Model Autopsy Autoradiography Binding Binding Sites Biological Assay Biological Markers Biological Models Biopsy Brain Brain imaging Brain region C9ORF72 Cells Chemicals Clinical Clinical Trials Cyclotrons Data Dementia Dermal Disease Docking Drosophila genus Drug Industry Drug Kinetics Elderly Environment Evaluation Event Foxes Frontotemporal Lobar Degenerations Funding Goals Half-Life Human Image Impaired cognition In Vitro Individual Industry Standard Label Lead Ligand Binding Ligands Logistics Magnetic Resonance Imaging Measurement Measures Metabolic Marker Methods Modeling Modification Monitor Motor Neurons Mus Neurodegenerative Disorders Nuclear Nucleic Acid Binding Pathogenesis Pathologic Pathology Patients Penetration Persons Pharmaceutical Chemistry Pharmaceutical Preparations Play Positron-Emission Tomography Preparation Process Production Property Proteins Public Health Quantitative Autoradiography RNA Binding RRM1 gene RRM2 gene Radiolabeled Radiopharmaceuticals Research Personnel Ribonucleotides Risk Rodent Role Safety Sampling Series Site Skin Sodium Chloride Specificity Specimen Statistical Data Interpretation Suggestion Syndrome TDP-43 aggregation Therapeutic Therapeutic Agents Therapeutic Effect Toxic effect Toxicology Transgenic Mice Transgenic Model Transgenic Organisms Translations Validation Work X-Ray Crystallography acronyms base blood-brain barrier penetration clinical diagnosis clinical translation disorder subtype dosimetry drug development epidemiologic data experience imaging agent imaging biomarker imaging study in vivo in vivo imaging induced pluripotent stem cell inhibitor insight lead candidate light scattering limbic-predominant age-related TDP-43 encephalopathy locomotor deficit motor neuron degeneration mouse model mutant nervous system disorder neuroimaging novel parent grant pre-clinical prevent prognostication programs promoter protein TDP-43 radioligand radiotracer scaffold scale up small molecule small molecule inhibitor success targeted treatment therapeutic target uptake

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 TDP-43 包含与 AD 患者认知能力下降相关的数据已被证实。被称为边缘主导型年龄相关性 TDP-43 脑病 (LATE) 以及其他缩写词，新认识到 TDP-43 在 AD 中的重要性（AD-TDP）是 AD 的最常见原因。中晚年认知障碍和痴呆症困扰着全球约 3000 万人对临床和病理学研究的广泛回顾表明，TDP-43 蛋白病与遗忘相关归因风险的统计分析表明 TDP-43 发生在老年人中。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% 这种 TDP-43 蛋白病是一种与其他 TDP-43 不同的临床和病理实体。也可以用 TDP-43 靶向治疗治疗的相关疾病，例如肌萎缩侧索硬化症因此，硬化症（ALS）和某些形式的额颞叶变性（FTLD-TDP）是成功的。该项目的完成有可能确定基于 TDP-43 的疗法用于治疗其他疾病我们发现了与 TDP-43 结合的小分子。 TDP-43 以这样的方式抑制 RNA 与 TDP-43 的结合并防止 TDP-43 聚集，具有活性提示在三种模型中具有治疗效果：（1）人类野生型和突变型 TDP-43 在果蝇，(2) 来自 C9orf72 患者来源的 iPSC 诱导的运动神经元 (iMN)，以及 (3) 表达表达的小鼠来自 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 RRM2 结合，该基序包含其中之一最近的一项 PET 成像研究表明，氨基酸参与了与 RRM1 的关键且功能相关的盐桥。描述了一种代谢标记物，可以根据 FDG 比率选择 AD-TDP 患者进行临床试验在这个项目中，我们寻求发现、验证和开发新的小脑区域成像。核酸结合 TDP-43 的分子抑制剂和 TDP-43 聚集抑制剂治疗 AD-TDP。图 1 是新型 TDP-43 配体的体外效力和类药特性（包括渗透）的优化使用综合药物电池进入大脑并采取可接受的半衰期和安全措施目标 2 涉及使用转染的 hTDP-43 进行靶点参与研究。 HEK293T 细胞、源自 iPSC 的患者诱导运动神经元、动态光散射分析目标 3 是在动物模型中评估与 TDP-43 结合的配体的聚集和 X 射线晶体学。 TDP-43 病理学，最初使用 Thy1 启动子，然后使用基于 hTDP-43 的小鼠模型目标 4 包括支持 IND 的研究，放大合成、多物种 PK 和啮齿动物毒性。