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

描述(申请人提供)：目前还没有治愈多发性硬化症(MS)的方法。目前可用的免疫调节治疗不能改变轴突变性的发病机制，而且在防止MS患者的永久性残疾积累方面只有部分有效。从理论上讲，找到一种可以刺激内源性髓鞘形成从而防止轴突退化的药物可以阻止疾病的进展。为此，我们最近发现，雌激素受体(ER)2配体二芳基丙腈(DPN)治疗可以诱导实验性自身免疫性脑脊髓炎(EAE)的功能性内源性再髓鞘形成。这是第一个已被证明在炎症存在的情况下激活重新髓鞘形成和逆转轴突损伤的药物。使用ER2配体的治疗在男性和女性中可能都很好地耐受，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而不是ER2来调节的。在最近发表的初步数据的指导下，我们希望从BASE(治疗EAE)过渡到床边(治疗MS)。这些研究的目标是确定FDA要求的ER2配体(DPN-Tcriis和SAR143953-Sanofi Avens)的活性、药代动力学和毒性，以推动化合物进入人体和临床试验。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ER2配体在MS小鼠模型中恢复脱髓鞘和神经变性轴突的关键时间窗口；以及在大鼠身上进行常规毒性研究，以确定该化合物的安全性。这项研究的结果将完成临床前开发管道中的初步步骤，这是开始使用ER2配体治疗以防止神经系统脱髓鞘和轴突损伤的临床测试所必需的。 公共卫生相关性：拟议研究的目标是分析雌激素受体(ER)2配体治疗多发性硬化症小鼠的神经保护作用的最小剂量、时间和持续时间。拟议的研究与公共健康相关，因为我们正在研究一种假定的治疗剂，它刺激内源性髓鞘形成，从而在脱髓鞘疾病期间提供临床保护。男性和女性对ER2配体的治疗耐受性很好，因为乳腺癌和子宫内膜癌都是通过ER1而不是ER2介导的。此外，ER2配体没有已知的毒性，一旦检测，可以迅速从实验室工作台移到床边。这项拟议的研究与NIH任务的一部分有关，该任务涉及神经系统疾病创新疗法的概念化、发现和临床前评估，目的是加速开发这些疾病的新疗法，以帮助减轻人类残疾的负担。 免责声明：请注意，以下批评是由评审员在研究小组会议之前准备的，基本上是以未经编辑的形式提供的。虽然审查员有机会根据小组的讨论更新或修订其书面评价，但不能保证在会议讨论之后更新了个别批评意见。因此，这些评论可能不能完全反映个别评审员在小组讨论结束时的最终意见或小组的最终多数意见。因此，讨论纪要和总结是审查员在会议上实际上认为至关重要的最后结论。

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.