Selection of a lead LPAR1 antagonist for treatment of diabetic neuropathy

选择用于治疗糖尿病神经病变的主要 LPAR1 拮抗剂

• 批准号: 10259568
• 负责人: Graham Beaton
• 金额: $ 103.58万
• 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: 2021-05-20 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259568
• 关键词: ADME Study; Alzheimer' s Disease; Analgesics; Behavioral; Biochemical; Biological Assay; Brain; California; Clinical Trials; Cytochrome P450; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic Neuropathies; Disease; Encephalopathies; Enzyme Inhibition; Evaluation; Exposure to; FDA approved; Functional disorder; Goals; Grant; Health; High Fat Diet; Hippocampus (Brain); Histologic; Impact evaluation; Impaired cognition; Insulin-Dependent Diabetes Mellitus; Laboratories; Lead; Lysophosphatidic Acid Receptors; Measures; Metabolic syndrome; Metabolism; Modeling; Morphology; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Pain; Pathogenicity; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Phase; Physiological; Process; Production; Rattus; Recommendation; Risk Factors; Rodent; Safety; Sampling; Spinal; Spinal Cord; Spinal Cord Diseases; Streptozocin; Structure; Synapses; Synaptophysin; Testing; Time; Tissues; Toxic effect; Translating; Type 2 diabetic; Universities; behavior measurement; behavioral study; diabetic; diabetic rat; drebrins; drug distribution; effective therapy; epigen; glycemic control; indexing; interest; nerve injury; nonhuman primate; novel; novel therapeutics; preclinical efficacy; preclinical study; prevent; safety assessment; safety study; scale up; screening; small molecule; symptom treatment; therapeutic candidate

PROJECT SUMMARY Diabetic neuropathy (DPN) is a major unmet health concern where over half of the estimated 33 million people in the US with type 1 or type 2 diabetes will develop neuropathy1. There is no FDA-approved disease modifying treatment for preventing or slowing progression of diabetic neuropathy other than a recommendation to maintain glycemic control2 and current treatments are restricted to management of the symptomatic consequences of neuropathy such as pain. It is becoming increasingly appreciated that diabetes also injures both the spinal cord (myelopathy) and brain (encephalopathy) such that diabetes is recognized as a prominent risk factor for developing cognitive dysfunction and Alzheimer’s disease14. Accordingly, agents that prevent or reverse peripheral nerve and/or CNS insults during diabetes are of interest either as standalone agents or for adjunctive use with symptomatic treatments. Epigen has developed expertise around the discovery and development of novel lysophosphatidic acid receptor type 1 (LPAR1) antagonists for the treatment of fibrotic disease. In parallel to the study of diabetic nephropathy data was obtained to suggest that lead compounds discovered at Epigen also benefit endpoints of diabetic neuropathy for both nerve injury and markers for cognitive decline in models. This proposal builds on these data to determine if one such lead compound, EPGN2154, may be developed to treat diabetic neuropathy. The goal of this direct to phase 2 application is to conduct detailed pre-clinical efficacy of EPGN2154 in rat DPN models, along with screening safety to allow nomination of a development candidate. Compounds will be prepared and characterized at Epigen prior to testing at University of California San Diego (UCSD) under the guidance of Dr. Nigel Calcutt. Dr. Calcutt’s laboratory will establish and maintain colonies of diabetic rodents, treat them with test agents provided by Epigen and measure physiological, behavioral and structural indices of peripheral and central neuropathy at assorted times throughout the study. Upon study completion tissue will be dissected and processed for histological and biochemical evaluation to support behavioral measurements. Epigen will conduct additional lead profiling to support candidacy of EPGN2154. Drug distribution will also be evaluated to support mechanistic studies. Compound profiling will include a safety assessment of EPGN2154. These studies will support the advancement of EPGN2154 to IND enabling studies as a prelude to entry into clinical trials for DPN.

项目概要 糖尿病神经病 (DPN) 是一个未得到满足的主要健康问题，估计有 3300 万人中有一半以上患有糖尿病神经病 (DPN) 在美国，患有 1 型或 2 型糖尿病的人会患上神经病1。目前尚无 FDA 批准的疾病修饰药物 除建议维持治疗外，用于预防或减缓糖尿病神经病变进展的治疗 血糖控制2和当前的治疗仅限于管理以下症状的后果 神经病变，例如疼痛。人们越来越认识到糖尿病也会损害脊髓 （脊髓病）和大脑（脑病），因此糖尿病被认为是以下疾病的一个重要危险因素： 发展认知功能障碍和阿尔茨海默病14。因此，预防或逆转的药物 糖尿病期间的周围神经和/或中枢神经系统损伤无论作为独立药物还是辅助药物都令人感兴趣 与对症治疗一起使用。 Epigen 围绕发现和开发开发了专业知识 新型溶血磷脂酸受体 1 型 (LPAR1) 拮抗剂，用于治疗纤维化疾病。并联 糖尿病肾病研究中获得的数据表明 Epigen 发现的先导化合物 还有益于糖尿病神经病变的神经损伤终点和模型中认知能力下降的标志物。 该提案以这些数据为基础，以确定是否可以开发一种这样的先导化合物 EPGN2154 治疗糖尿病神经病变。这种直接进入二期应用的目标是进行详细的临床前疗效 EPGN2154 在大鼠 DPN 模型中的作用，以及筛选安全性以允许提名开发候选者。 化合物将在 Epigen 进行制备和表征，然后在加州大学圣地亚哥分校进行测试 （加州大学圣地亚哥分校）在奈杰尔·卡尔卡特博士的指导下。卡尔卡特博士的实验室将建立并维持 糖尿病啮齿动物，用 Epigen 提供的测试剂对其进行治疗，并测量其生理、行为和 在整个研究的不同时间周围和中枢神经病变的结构指数。经过学习 完成后的组织将被解剖和处理以进行组织学和生化评估，以支持 行为测量。 Epigen 将进行额外的先导物分析以支持 EPGN2154 的候选资格。药品 还将评估分布以支持机制研究。化合物分析将包括安全性 EPGN2154 的评估。这些研究将支持 EPGN2154 向 IND 赋能研究的进展 作为进入 DPN 临床试验的前奏。