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

用于治疗和预防耐药性癫痫发作的研究性 WNT 通路调节剂

• 批准号: 10725450
• 负责人: Melissa Leigh Barker-Haliski
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725450
• 关键词: Acute; Address; Adult; Affect; Animal Model; Animals; Anticonvulsants; Antiepileptogenic; Behavior assessment; Biological Assay; Bone Growth; Brain; Caring; Chemicals; Chronic; Clinical; Cornea; Data; Development; Disease; Dose; Drug resistance; Electroconvulsive Shock; Electroencephalography; Epilepsy; FDA approved; Female; Focal Seizure; Goals; Harvest; Homeostasis; Individual; Intractable Epilepsy; Investigational Therapies; Levetiracetam; Life; Locomotion; Marketing; Medical; Methodology; Modeling; Molecular Target; Mus; Neurologic; Neurons; Oral Administration; Organ; Outcome; Pathway interactions; Patients; Pentylenetetrazole; Peripheral; Persons; Pharmaceutical Preparations; Phase; Plasma; Prevention; Published Comment; Rattus; Recurrence; Resistance; Risk; Rodent; Rodent Model; Route; Seizures; Severities; Signal Transduction; Status Epilepticus; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxicology; Valproic Acid; WNT Signaling Pathway; Work; acquired epilepsy; behavioral impairment; beta catenin; clinically relevant; cohort; drug market; drug repurposing; drug standard; effective therapy; habituation; indexing; intraperitoneal; male; motor impairment; mouse model; nervous system development; novel; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; preventable epilepsy; screening; small molecule; standard of care; subcutaneous; symptom treatment; tumor

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.

抽象的 已经确定了许多有前途的研究疗法用于治疗癫痫的治疗 建立了癫痫发作和癫痫的动物模型已有80多年了。在此期间，最大电动摇滚 在小鼠和大鼠中进行测试，小鼠和大鼠的皮下五苯甲酸测试以及6 Hz 在小鼠中的测定，全部被用作电或化学诱发癫痫发作的主要模型 神经学完整的啮齿动物。此外，啮齿动物点燃模型，在该模型中，网络过时的性能具有 开发的，已用于识别新的和高度影响力的代理，例如左乙烯塔姆。此筛选 方法已成功确定了几种销售药物来管理与症状癫痫发作有关的症状 癫痫。尽管当今市场上有大量的抗性药物（ASD），但有近30％的患者 癫痫对这些目前可用的药物具有抵抗力。此外，尚未确定 放慢或完全防止癫痫的发展。为了满足这种未满足的医疗需求，更有效 癫痫患者仍然需要更好的耐受性治疗。我们的小组有 最近发现了接合未开发的几种重新利用的治疗剂的抗性功效 与正常神经系统发育和成年期组织稳态相关的分子靶标。 此外，我们已经在诱发的慢性癫痫发作的小鼠模型中证明了 重新利用的药物耐受性良好，可能会破坏过度可观的神经元的形成 网络，表明可能改变疾病的作用。因此，这项研究将扩展抗性 这两种有希望的研究化合物的功效概况，用于治疗症状性癫痫发作 建立药代动力学和药效的关系，并评估其防止的潜力 癫痫症完全由公认的啮齿动物癫痫发作和癫痫模型。我们将使用临床相关的老鼠 获得的癫痫的模型，该模型提供了一个有效的平台，可以在该平台上评估改良疾病的潜力 两种有前途的候选化合物。这项研究旨在进一步表征两个 有望治疗急性癫痫发作的有希望的化合物，并定义了治疗的程度 修改自发癫痫发作的发作，即证明癫痫是否延迟或 阻止。此外，这项研究将确定使用新颖的重新使用剂是否具有有希望的使用 初步疗效特征表明，有可能成为治疗的第一类疗法，并且 可能预防，癫痫。