Development of a galanin-based therapy for the treatment of refractory epilepsy

开发基于甘丙肽的难治性癫痫疗法

基本信息

批准号：
8135222
负责人：
H Steve WHITE
金额：
$ 96.49万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8135222
关键词：
ADME Study Acids Affect Affinity Anatomy Animal Model Animals Anticonvulsants Antiepileptic Agents Behavioral Biological Assay Biological Availability Blood - brain barrier anatomy Blood Glucose Bolus Infusion Brain Cardiovascular system Cheese Chemistry Chronic Clinical Clinical Research Clinical Trials Cognitive Cornea Cytochrome P450 Data Development Development Plans Disease Documentation Dose Drug Formulations Drug Interactions Drug Kinetics Epilepsy Evaluation GALR2 Galanin Receptor Galanin Gated Ion Channel Goals Half-Life Hour Human Impairment In Vitro Inhibitory Concentration 50 Injection of therapeutic agent Intravenous Isoenzymes Kindling (Neurology)Lead Learning Ligand Binding Measures Memory Metabolic Modeling Molecular Target Mus Neuraxis Neuropeptides Outcome Pamphlets Partial Epilepsies Pathology Patients Pentylenetetrazole Peptides Performance Persons Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Plasma Play Preparation Principal Investigator Protein Isoforms Protocols documentation Rattus Refractory Reporting Research Personnel Research Proposals Resistance Role Rotarod Performance Test Safety Screening procedure Seizures Series Solubility Somatotropin Specificity Staging Technology Testing Therapeutic Time Toxic effect Toxicology Translational Research Vertebral column analog analytical method base design experience galanin receptor human subject in vivo meetings morris water maze motor impairment mouse model new technology nonhuman primate novel novel strategies phase 1 study pre-clinical preclinical study programs public health relevance receptor receptor binding research clinical testing respiratory response safety study subcutaneous success therapeutic target voltage

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this Translational Research Proposal is to synthesize, characterize, and advance an optimized galanin-based analog to IND filing so that a human proof-of-concept clinical trial with a novel first-in-class therapeutic can be conducted in patients with refractory epilepsy. Most of the available antiepileptic drugs (AEDs) exert their activity by modulating voltage- and/or receptor-gated ion channels. Despite treatment with currently available AEDs, approximately 25-40% of patients with refractory partial epilepsy continue to experience uncontrolled seizures, so clearly there is a need for a novel approach. The endogenous neuropeptide galanin and its associated receptors play an important role in the control of seizures and is therefore an attractive therapeutic target. However, developing neuropeptides as therapeutics has been challenging due to their intrinsic lack of metabolic stability and inability to cross the blood-brain-barrier. We have applied a novel technology platform to develop a galanin analog, NAX 5055, that is metabolically stable, maintains low nanomolar affinity for galanin receptors and following systemic administration is effective in an animal seizure model that displays resistance to the majority of first-line AEDs. The Aims outlined in this proposal are designed to optimize the NAX 5055 backbone and to advance one compound to an IND filing as follows: 1) identify one to six optimized galanin receptor 2-preferring analogs that display potent anticonvulsant activity and wide behavioral, cognitive and metabolic safety margins; 2) select at least one IND candidate based on the most favorable pharmacological and ADME profiles; 3) develop a formulation that maintains efficacy in animal models following systemic administration and is suitable for further preclinical and clinical development; 4) and 5) perform all necessary IND-enabling preclinical studies. Successful completion of Aims 1 - 5 will allow the development of a clinical plan and submission of an IND application with the FDA to begin clinical trials of a new, first-in-class neurotherapy for refractory epilepsy. PUBLIC HEALTH RELEVANCE: Epilepsy affects over 50 million persons world-wide and approximately 25-40% of refractory partial epilepsy patients have uncontrolled seizures despite treatment with antiepileptic drugs. Galanin is an endogenous peptide in the brain that plays an important role in controlling seizures. The goal of this proposal is to apply our proprietary technology to develop a novel galanin-based therapy for treating this debilitating disorder.

描述（由申请人提供）：该转化研究提案的总体目标是合成、表征和推进一种优化的基于甘丙肽的类似物以提交 IND 申请，以便进行人体概念验证临床试验，并具有新颖的首创性可以对难治性癫痫患者进行类治疗。大多数可用的抗癫痫药物 (AED) 通过调节电压和/或受体门控离子通道发挥其活性。尽管使用目前可用的 AED 进行治疗，但大约 25-40% 的难治性部分性癫痫患者仍会出现无法控制的癫痫发作，因此显然需要一种新的方法。内源性神经肽甘丙肽及其相关受体在控制癫痫发作中发挥着重要作用，因此是一个有吸引力的治疗靶点。然而，由于神经肽本身缺乏代谢稳定性且无法穿过血脑屏障，因此开发神经肽作为治疗药物一直具有挑战性。我们应用了一种新颖的技术平台来开发甘丙肽类似物 NAX 5055，该药物代谢稳定，对甘丙肽受体保持低纳摩尔亲和力，全身给药后在动物癫痫模型中有效，该模型对大多数一线 AED 表现出耐药性。该提案中概述的目标旨在优化 NAX 5055 主链，并将一种化合物推进 IND 备案，如下：1) 确定一到六种优化的甘丙肽受体 2 偏好类似物，这些类似物显示出有效的抗惊厥活性和广泛的行为、认知和代谢安全裕度； 2) 根据最有利的药理学和 ADME 概况选择至少一种 IND 候选药物； 3）开发一种在动物模型中全身给药后仍能保持疗效并适合进一步临床前和临床开发的制剂； 4) 和 5) 执行所有必要的 IND 临床前研究。成功完成目标 1 - 5 将允许制定临床计划并向 FDA 提交 IND 申请，以开始针对难治性癫痫的新型一流神经疗法的临床试验。公共卫生相关性：全球有超过 5000 万人患有癫痫症，尽管使用抗癫痫药物治疗，但约 25-40% 的难治性部分性癫痫患者的癫痫发作仍无法控制。甘丙肽是大脑中的一种内源性肽，在控制癫痫发作方面发挥着重要作用。该提案的目标是应用我们的专有技术开发一种新型的基于甘丙肽的疗法来治疗这种使人衰弱的疾病。