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

描述（由申请人提供）：目前没有治愈多发性硬化症（MS）的方法。目前可用的免疫调节疗法不能改变轴突变性的发病机制，并且在预防多发性硬化症患者永久性残疾积累方面仅部分有效。找到一种药物，刺激内源性髓鞘形成，从而防止轴突退化，理论上可以阻止疾病的进展。为此，我们最近发现用雌激素受体（ER） 2配体二芳基丙腈（DPN）治疗实验性自身免疫性脑脊髓炎（EAE）可诱导功能性内源性髓鞘再生。这是第一个被证明可以激活髓鞘再生和逆转炎症中轴突损伤的药物。用ER2配体治疗可能在男性和女性中耐受良好，因为女性的生殖行为以及乳腺癌和子宫内膜癌都是通过ER1介导的，而不是ER2。在最近发表和初步数据的指导下，我们希望从实验室（EAE治疗）过渡到床边（MS治疗）。这些研究的目的是确定FDA要求的ER2配体（DPN-Tocris和sar143953 -赛诺菲安万特）的生存能力、药代动力学和毒性，以便将这些化合物推进人体和临床试验。本研究的目的是：确定能有效刺激内源性髓鞘形成和恢复功能性轴突传导的ER2配体的最低剂量；评估MS小鼠模型中ER2配体在疾病期间恢复脱髓鞘和神经退行性轴突的关键时间窗口；并在大鼠身上进行常规毒性研究以确定该化合物的安全性。从该研究中获得的结果将完成临床前开发的初步步骤，以开始临床测试ER2配体治疗以防止神经系统脱髓鞘和轴突损伤。

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. PUBLIC HEALTH RELEVANCE: The goals of the proposed research are to analyze the minimum dose, timing, and duration of neuroprotective effect conferred by treatment with an estrogen receptor (ER)2 ligand in a mouse model of MS. The proposed research is relevant to public health because we are examining a putative therapeutic agent that stimulates endogenous myelination resulting in sparing of axons and clinical protection during demyelinating disease. Treatment with the ER2 ligand would likely be very well tolerated in males and females as both breast and uterine endometrial cancer are mediated through ER1, not ER2. In addition, ER2 ligand has no known toxicity and once tested could be rapidly moved from the laboratory bench to the bedside. The proposed research is relevant to the part of NIH's mission that pertains to the conceptualization, discovery, and preclinical evaluation of innovative therapeutics for nervous system disorders, with the goal of accelerating the development of new treatments for these diseases that will help to reduce the burdens of human disability. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.