Investigational WNT-pathway modulators for the treatment and prevention of drug-resistant seizures

摘要 许多有前途的研究性治疗癫痫的方法已经确定使用良好的- 建立癫痫发作和癫痫动物模型已有80余年。在这段时间里，最大的电击 在小鼠和大鼠中的皮下戊四唑试验，以及最近的6 Hz 在小鼠中的试验，都被用作电或化学诱发癫痫发作的主要模型， 神经系统完好的啮齿类动物此外，啮齿动物点燃模型，其中网络过度兴奋， 已开发的新的和高影响力的药物，如左乙拉西坦。该筛选 这种方法已经成功地确定了几种上市药物，以管理与癫痫发作相关的症状 患有癫痫尽管目前市场上有许多抗癫痫药物（ASD），但近30%的ASD患者 癫痫对目前可用的这些药物有抗药性。此外，尚未确定治疗方法， 减缓或完全阻止癫痫的发展。为了解决这一未满足的医疗需求， 癫痫患者仍然迫切需要更好的耐受性治疗。我们集团 最近发现了几种重新利用的治疗药物的抗癫痫疗效， 与成年期正常神经系统发育和组织稳态相关的分子靶点。 此外，我们已经证明，在诱发慢性癫痫发作的小鼠模型中， 重新利用的药物耐受性良好，可能会破坏过度兴奋神经元的形成， 网络，表明可能的疾病修饰作用。因此，这项研究将扩大抗癫痫 这两种有前景的研究化合物治疗症状性癫痫发作的疗效概况， 建立药代动力学和药效学关系，并评估其预防 癫痫发作和癫痫模型中的癫痫。我们将使用临床相关的大鼠 获得性癫痫模型，提供了一个有效的平台，在此基础上评估疾病改善潜力 两种有希望的候选化合物本研究旨在进一步表征两种药物的治疗潜力。 用于治疗急性癫痫发作的有前途的化合物，以及定义治疗的程度 改变自发性复发性癫痫发作的发作，即，证明癫痫是否延迟或 防止。此外，这项研究将确定是否使用新的重新用途的药物， 初步疗效特征表明，有可能成为治疗的一流疗法， 可能是为了预防癫痫。

ABSTRACT Numerous promising investigational therapies for the treatment of epilepsy have been identified using well- established animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have all been utilized as primary models of electrically or chemically evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which network hyperexcitability has developed, have been used to identify new and highly impactful agents, such as levetiracetam. This screening approach has successfully identified several marketed drugs to manage the symptomatic seizures associated with epilepsy. Despite the numerous antiseizure drugs (ASDs) on the market today, nearly 30% of patients with epilepsy are resistant to these currently available medications. Further, no treatment has yet been identified to slow or prevent the development of epilepsy altogether. To address this unmet medical need, more effective and better tolerated treatments are still desperately needed by the patient with epilepsy. Our group has recently uncovered the antiseizure efficacy of several repurposed therapeutic agents that engage untapped molecular targets associated with normal nervous system development and tissue homeostasis in adulthood. Further, we have demonstrated in a mouse model of evoked chronic seizures that repeated administration of repurposed agents is well-tolerated and can possibly disrupt the formation of a hyperexcitable neuronal network, suggesting a possible disease modifying effect. This study will therefore extend the antiseizure efficacy profile of these two promising investigational compounds for the treatment of symptomatic seizures to establish a pharmacokinetic and pharmacodynamic relationship, as well as assess their potential to prevent epilepsy altogether in well-established rodent seizure and epilepsy models. We will use a clinically relevant rat model of acquired epilepsy that provides a valid platform on which to evaluate the disease-modifying potential of two promising candidate compounds. This study aims to further characterize the therapeutic potential of two promising compounds for the treatment of acute seizures, as well as define the extent to which treatment modifies the onset of spontaneous recurrent seizures, i.e., demonstrate whether epilepsy is delayed or prevented. Further, this study will determine whether the use of novel repurposed agents with promising preliminary efficacy profiles demonstrate the potential to be first-in-class therapies for the treatment, and possibly prevention, of epilepsy.