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Evaluation of Alzheimers disease experimental small molecule therapeutics in the models of Amyotrophic lateral sclerosis

阿尔茨海默病实验性小分子疗法在肌萎缩侧索硬化症模型中的评价

基本信息

批准号：
10259064
负责人：
Satheesh B Ravula
金额：
$ 45万
依托单位：
EPIGEN BIOSCIENCES, 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：
2021-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259064
关键词：
Adult Age Agonist Alanine Alzheimer&apos s Disease Alzheimer&apos s disease model Amyotrophic Lateral Sclerosis Autopsy Axon Biological Biological Availability Body Weight Brain Brain region Brain-Derived Neurotrophic Factor Cell Survival Cessation of life Chromosome 9 Clinical Codon Nucleotides Cognition DNA Sequence Alteration DNA-Binding Proteins Data Dendrites Development Disease model Dose Drug Exposure Electromyography Endoplasmic Reticulum Evaluation Feasibility Studies Female G-Protein-Coupled Receptors Genes Glycine Grant Hand High Pressure Liquid Chromatography Histology Hour Human Lead Letters Ligands Literature Maximum Tolerated Dose Modeling Molecular Chaperones Monitor Motor Neurons Mus Muscular Atrophy Nerve Degeneration Neuraxis Neurites Neurodegenerative Disorders Neurons Neuroprotective Agents Neurotransmitters Oral Paralysed Pharmacotherapy Phase Phenotype Plasma Play Preparation Process Progress Reports Proteins Reporting Research Design Role Rotarod Performance Test Small Business Innovation Research Grant Spinal Spinal Cord Strategic Planning System The Jackson Laboratory Time TimeLine Tissue Sample Toxicology Transact Transgenic Mice Whole Blood Work amyotrophic lateral sclerosis therapy efficacy evaluation efficacy outcomes efficacy study experimental group experimental study familial amyotrophic lateral sclerosis fused in sarcoma improved induced pluripotent stem cell lead optimization male mouse model mutant neuroprotection novel programs protein TDP-43 receptor response sample collection scale up sciatic nerve sex sigma-1 receptor small molecule small molecule therapeutics superoxide dismutase 1 synaptogenesis therapy development tool

项目摘要

Abstract The endoplasmic reticulum (ER) protein sigma-1 receptor represents a unique chaperone activity in the central nervous system, and it exerts a potent influence on several neurotransmitter systems. S1R is distinct from GPCRs and ionotropic receptors and is expressed in neurons in multiple brain regions in post-mortem human brains. S1R plays a modulatory role in biological mechanisms associated with neurodegeneration. S1R ligands activation is known to improve cognition, promote cell survival, and facilitate the release of the neuroprotectant BDNF. The broad objective is to evaluate selective sigma1 receptor (S1R) ligands toward commercial development for the treatment of Amyotrophic Lateral Sclerosis (ALS). During feasibility studies under grant R41AG043243, we identified EPGN644, a selective S1R small molecule ligand with CNS exposure with demonstrated efficacy in mouse models of AD (Tg4510) upon oral dosing. Lead optimization efforts identified EPGN2544 and EPGN2665 as alternatives to EPGN644 with a superior overall profile and with the novel composition of matter claims. Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by progressive muscle atrophy and paralysis due to the death of upper and lower Motor Neurons. The broad objective is to evaluate selective sigma1 receptor ligands toward commercial development for the treatment of ALS. A recent report indicated that PRE-084, a Sigma1R literature tool compound, demonstrated neuroprotection, neurite elongation, and efficacy in a SOD1G93A mouse model of ALS. Taking together this literature precedence for the benefit of S1R ligands in an ALS mouse model, and having a well-optimized S1R ligand (EPGN2665) in hand, we propose to conduct efficacy studies in human induced pluripotent stem cells (iPSC) derived motor neurons, and in two widely used mouse models of ALS (TDP-43 and SOD1G93A).

抽象的内质网 (ER) 蛋白 sigma-1 受体代表中枢的独特伴侣活性神经系统，并对多种神经递质系统产生有效影响。 S1R 不同于 GPCR 和离子型受体，在死后人类多个大脑区域的神经元中表达大脑。 S1R 在与神经退行性变相关的生物机制中发挥调节作用。 S1R配体已知激活可以改善认知、促进细胞存活并促进神经保护剂的释放脑源性神经营养因子。广泛的目标是评估选择性 sigma1 受体 (S1R) 配体的商业开发肌萎缩侧索硬化症（ALS）的治疗。在 R41AG043243 拨款的可行性研究期间，我们鉴定出 EPGN644，一种具有中枢神经系统暴露的选择性 S1R 小分子配体，在口服给药后的 AD (Tg4510) 小鼠模型。已确定 EPGN2544 和 EPGN2665 的先导化合物优化工作作为 EPGN644 的替代品，具有卓越的整体轮廓和新颖的物质成分声明。肌萎缩侧索硬化症 (ALS) 是一种成人发病的神经退行性疾病，其特征为进行性由于上、下运动神经元死亡而导致肌肉萎缩和瘫痪。总体目标是评估选择性 sigma1 受体配体对 ALS 治疗的商业开发。最近的一个报告表明，Sigma1R 文献工具化合物 PRE-084 表现出神经保护作用，神经突 ALS SOD1G93A 小鼠模型的伸长率和功效。将这些文献的优先顺序汇总起来 S1R 配体在 ALS 小鼠模型中的益处，并且手头有经过良好优化的 S1R 配体 (EPGN2665)，我们建议对人类诱导多能干细胞（iPSC）衍生的运动神经元进行功效研究，以及两种广泛使用的 ALS 小鼠模型（TDP-43 和 SOD1G93A）。