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.

项目总结