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

• 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
• 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' s Disease; Alzheimer' 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

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).

摘要 内质网(ER)蛋白Sigma-1受体代表了中枢神经系统中一种独特的伴侣活性 它对几个神经递质系统有很大的影响。S1R不同于 GPCRs和趋离子受体在人死后多个脑区神经元中的表达 大脑。S1R在神经退行性变相关的生物学机制中起着调节作用。S1R配体 众所周知，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 BDNF。 广泛的目标是评估选择性S1R配体的商业化开发 肌萎缩侧索硬化症的治疗。在R41AG043243资助下的可行性研究期间，我们 鉴定了EPGN644，一种选择性的S1R小分子配体，与中枢神经系统暴露，在 灌胃给药建立AD小鼠模型(Tg4510)。主导优化工作，确定了EPGN2544和EPGN2665 作为EPGN644的替代品，具有优越的整体轮廓和新颖的物质构成要求。 肌萎缩侧索硬化症(ALS)是一种成人起病的神经退行性疾病，其特征是进行性 由于上下运动神经元的死亡而导致的肌肉萎缩和瘫痪。其总体目标是 评估选择性Sigma1受体配体用于ALS治疗的商业化开发。最近 报告表明，Sigma1R文献工具化合物Pre-084显示出神经保护作用，突起 在ALS的SOD1G93A小鼠模型中的延伸性和有效性。把这部文学作品放在一起， 肌萎缩侧索硬化症小鼠模型中S1R配体的益处，并且手中有一个优化良好的S1R配体(EPGN2665)， 我们建议在人诱导多能干细胞(IPSC)来源的运动神经元中进行有效性研究， 在两种广泛使用的ALS小鼠模型(TDP-43和SOD1G93A)中也有表达。