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：
8730716
负责人：
H Steve WHITE
金额：
--
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/8730716
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 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 screening 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.

描述（由申请人提供）：这项翻译研究建议的总体目标是综合，表征和推进一个基于优化的Galanin基于IND的类似物，以便通过新颖的首次首次进行概念证明临床试验可以在难治性癫痫患者中进行类治疗。大多数可用的抗癫痫药（AED）通过调节电压和/或受体门控离子通道发挥其活性。尽管目前可用的AED治疗，但约有25-40％的难治性部分癫痫患者继续经历不受控制的癫痫发作，因此显然需要采用一种新颖的方法。内源性神经肽葡萄蛋白及其相关受体在控制癫痫发作中起着重要作用，因此是一个有吸引力的治疗靶标。然而，由于其内在缺乏代谢稳定性和无法穿越血脑屏障的缺乏，因此将神经肽作为治疗剂构成了挑战。我们已经应用了一个新型的技术平台来开发galanin类似物NAX 5055，该平台是代谢稳定的，保持低纳摩尔亲和力对Galanin受体，并且随后全身给药在动物癫痫发作模型中有效地表现出对大多数一线AED的抵抗力。本提案中概述的目的旨在优化NAX 5055骨架，并将一种化合物推向IND归档，如下所示：1）识别一到六个优化的Galanin受体2优先类似物，这些类似物表现出有效的抗惊厥活性和广泛的行为，认知和认知，认知和认知，并且代谢安全边缘； 2）至少根据最有利的药理和ADME概况选择一个IND候选者； 3）开发一种制定的制剂，该公式在全身给药后保持动物模型的功效，适合进一步的临床前和临床发育； 4）和5）执行所有必要的指定临床前研究。成功完成目标1-5将允许制定临床计划，并在FDA中提交IND应用程序，以开始对新的，一类神经疗法进行难治性癫痫的临床试验。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The anticonvulsant action of the galanin receptor agonist NAX-5055 involves modulation of both excitatory- and inhibitory neurotransmission.

甘丙肽受体激动剂 NAX-5055 的抗惊厥作用涉及兴奋性和抑制性神经传递的调节。

DOI：
10.1016/j.eplepsyres.2016.01.006
发表时间：
2016
期刊：
Epilepsy research
影响因子：
2.2
作者：
Walls,AnneB;Flynn,SeanP;West,PeterJ;Müller,MargitS;Bak,LasseK;Bulaj,Grzegorz;Schousboe,Arne;White,HSteve
通讯作者：
White,HSteve

Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2.