Estrogen receptor B ligand: A novel treatment to enhance functional remyelination

雌激素受体 B 配体：一种增强功能性髓鞘再生的新疗法

基本信息

批准号：
8289411
负责人：
Seema K Tiwari-Woodruff
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8289411
关键词：
Aftercare Animal Model Anti-Inflammatory Agents Anxiety Axon Biodistribution Brain Breast Cardiac Chemical Agents Clinic Clinical Clinical Trials Cognitive Critiques Data Demyelinating Diseases Demyelinations Development Disease Disease Progression Dose Drug Delivery Systems Drug Kinetics Endometrial Carcinoma Estrogen Receptor 2 Estrogen Receptors Evaluation Experimental Autoimmune Encephalomyelitis Female Goals Hepatic Human Individual Inflammation Injury Kidney Laboratories Learning Ligands Long-Term Effects Mediating Memory Mental Depression Mission Motor Motor Skills Multiple Sclerosis Nerve Degeneration Nervous system structure Neuroglia Neurologic Neurons Neuroprotective Agents Oligodendroglia Oral Administration Organ Pathogenesis Patients Pharmaceutical Preparations Plasma Property Public Health Publishing Rattus Relapse Reproductive Behavior Research Safety Staging Study Section Testing Therapeutic Therapeutic Agents Time Toxic effect Treatment Effectiveness Update Writing axonal degeneration base bench to bedside body system design diarylpropionitrile disability dosage good laboratory practice innovation interest male meetings mouse model myelination nervous system disorder novel pre-clinical preclinical evaluation prevent remyelination reproductive research clinical testing respiratory safety study

项目摘要

DESCRIPTION (provided by applicant): There is presently no cure for multiple sclerosis (MS). Currently available immunomodulatory therapies do not modify the pathogenesis of axonal degeneration once it is established and are only partially effective in preventing permanent disability accumulation in MS patients. Identifying a drug that stimulates endogenous myelination and thereby prevents axon degeneration could theoretically halt disease progression. To this end we have recently discovered that treatment with an estrogen receptor (ER) 2 ligand diarylpropionitrile (DPN) can induce functional endogenous remyelination in experimental autoimmune encephalomyelitis (EAE). This is the first pharmacological agent that has been shown to activate remyelination and to reverse axon damage in the presence of inflammation. Treatment with the ER2 ligands would likely be very well tolerated in males and females as both reproductive behavior in females as well as breast and uterine endometrial cancer are mediated through ER1, not ER2. Guided by recently published and preliminary data we would like to make the transition from bench (treatment of EAE) to bedside (treatment of MS). The goal of these studies is to determine the viability, pharmacokinetics and toxicity of ER2 ligands (DPN-Tocris and SAR143953-Sanofi Aventis) required by the FDA to move the compounds forward into testing in humans and in the clinic. The goals of this study are: to determine the lowest dose of ER2 ligands that can effectively stimulate endogenous myelination and restore functional axon conduction; to assess the critical window of time during disease during which ER2 ligands can restore demyelinated and neurodegenerative axons in a mouse model of MS; and to conduct conventional toxicity studies in rat to determine the safety of the compound. The results obtained from the study will complete the preliminary steps in the pipeline for pre-clinical development necessary to begin clinical testing of treating with ER2 ligands to prevent demyelination and axon injury in the nervous system.

描述（由申请人提供）：目前无法治愈多发性硬化症（MS）。当前可用的免疫调节疗法建立后不会改变轴突变性的发病机理，并且仅在防止MS患者的永久性残疾积累方面有效。鉴定一种刺激内源性髓鞘化的药物，从而防止轴突变性理论上会停止疾病的进展。为此，我们最近发现，用雌激素受体（ER）2配体日二二硫二硫二硫二硫酸（DPN）治疗可以在实验性自身免疫性脑脊髓炎（EAE）中诱导功能性内源性再生。这是第一种药理学剂，已显示出在炎症存在下激活透明式化并逆转轴突损伤。在男性和女性中，用ER2配体的治疗可能会很好地耐受性，因为女性以及乳腺癌和子宫子宫内膜癌的生殖行为均通过ER1而不是ER2介导。在最近发布和初步数据的指导下，我们想从长凳（EAE）到床边（MS的处理）过渡。这些研究的目的是确定ER2配体（DPN-Tocris和SAR143953-Sanofi Aventis）的生存力，药代动力学和毒性，FDA需要将化合物向前移动到人类和临床中的测试。这项研究的目标是：确定可以有效刺激内源性髓鞘并恢复功能轴突传导的ER2配体的最低剂量；为了评估疾病期间的关键时间窗口，在此期间，ER2配体可以在MS小鼠模型中恢复脱髓鞘和神经退行性轴突；并在大鼠中进行常规毒性研究以确定化合物的安全性。从研究中获得的结果将完成管道中的初步步骤，以开始使用ER2配体进行临床测试所需的临床前开发，以防止神经系统中的脱髓鞘和轴突损伤。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis.

DOI：
10.1002/brb3.174
发表时间：
2013-11
期刊：
BRAIN AND BEHAVIOR
影响因子：
3.1
作者：
Moore, Spencer;Khalaj, Anna J.;Yoon, JaeHee;Patel, Rhusheet;Hannsun, Gemmy;Yoo, Timothy;Sasidhar, Manda;Martinez-Torres, Leonardo;Hayardeny, Liat;Tiwari-Woodruff, Seema K.
通讯作者：
Tiwari-Woodruff, Seema K.