Stimulating oligodendrocyte progenitor cell differentiation and remyelination

描述（由申请方提供）：目前可用的免疫调节疗法一旦确立，就不能调节轴突变性的发病机制，并且在预防MS患者发生永久性残疾方面仅部分有效。确定一种刺激内源性髓鞘形成和避免轴突变性的药物，理论上可以降低疾病进展的速度。我们以前已经表明，雌激素受体（ER）B配体治疗脱髓鞘小鼠模型;二芳基丙腈（DPN）有可能实现这一作用。由于DPN是一种低特异性的通用ERb配体， 筛选出特异性较高的ERb配体，并发现吲唑-Cl是最佳的ERb配体。目的是在多发性硬化（MS）动物模型中实现原理的体内验证，以确定开发候选药物吲唑-Cl治疗MS的可行性。使用最佳给药方案，预期吲唑-Cl对刺激内源性少突胶质细胞（OL）祖细胞（OPC）存活和分化、轴突髓鞘再生和神经保护的直接作用。将通过第二信使信号传导和靶细胞类型研究作用机制。将使用平移相关成像来可视化慢性MS小鼠模型中的效应。此外，将评估吲唑-Cl诱导的血清细胞因子和生长因子变化，以确认潜在的生物标志物和临床应用。最终，将进行安全性研究，以支持临床前候选人提名和档案完成。拟议的研究受到了吲唑-Cl强大的档案和令人鼓舞的初步结果的启发，这些结果证明了其在慢性MS小鼠模型中的治疗效果。具体而言，观察到内源性髓鞘再生的刺激和改善的轴突功能和神经学结果，并且似乎由增加的常驻OPC存活和分化介导。静止OPCs存在于MS病变中，并且不能被主要是免疫调节的当前MS药物有效激活。我们的目标是使用吲唑-Cl靶向内源性OPC，从而开发MS治疗，通过间歇性短期给药方案减缓疾病进展。

DESCRIPTION (provided by applicant): Currently available immunomodulatory therapies do not modulate the pathogenesis of axonal degeneration once it is established and are only partially effective in preventing the onset of permanent disability in MS patients. Identifying a drug that stimulates endogenous myelination and spares axon degeneration would theoretically reduce the rate of disease progression. We have previously shown that treatment of demyelinating mouse models with estrogen receptor (ER)b ligand; diarylpropionitrile (DPN) has the potential for fulfilling this role. Because DPN is a generic ERb ligand with low specificity we screened higher specificity ERb and found that Indazole-Cl was the best ERb ligand. The objective is to achieve in vivo proof of principle in multiple sclerosis (MS) animal models to establish feasibility of the development candidate Indazole-Cl for MS treatment. Using the optimal dosing regimen, a direct effect of Indazole-Cl on stimulation of endogenous oligodendrocyte (OL) progenitor cell (OPC) survival and differentiation, axon remyelination, and neuroprotection is expected. Mechanisms of action will be investigated via second messenger signaling and target cell type. Translationally-relevant imaging will be used to visualize effects n a chronic MS mouse model. Moreover, assessment of Indazole-Cl-induced changes in serum cytokine and growth factors will be assessed to confirm potential biomarkers and clinical application. Eventually, safety studies to support pre-clinical candidate nomination and dossier completion will be performed. The proposed research is inspired by Indazole-Cl's strong dossier and encouraging preliminary results demonstrating its therapeutic efficacy in a chronic MS mouse model. Specifically, stimulation of endogenous remyelination and improved axon function and neurological outcomes were observed and appear mediated by increased resident OPC survival and differentiation. Quiescent OPCs exist in MS lesions and are not effectively activated by largely immunomodulatory current MS drugs. We aim to target endogenous OPCs using Indazole-Cl, thereby developing MS treatment that slows disease progression with intermittent, short-term dosing regimens.