Ivermectin and human glycine receptor suppression of pharmacoresistant epilepsy

描述（由申请人提供）： 在过去的二十年中，旨在改善癫痫发作的药理学治疗的现代药物发现研究已经产生了十几种新的抗癫痫药物（AED）。尽管这些新的AED可能具有减少的副作用和药物-药物相互作用，但是在用新的AED治疗时继续具有癫痫发作的癫痫患者的百分比保持在30-40%，持续>20年。在这项提案中，我们的目标是开发一种基因治疗方法，通过实施一种新的“设计者”受体系统来治疗药物耐药性癫痫，该系统不应影响正常的脑功能，因此不太可能产生显著的副作用。该系统将利用腺相关病毒（AAV）递送经修饰的人1甘氨酸受体，其具有降低的甘氨酸敏感性和增强的对FDA批准的药物伊维菌素的敏感性。重组AAV将被遗传优化以在癫痫神经元中表达，并在癫痫动物模型中测试功效。伊维菌素在激活修饰受体所需的非常低的浓度下对正常大脑具有最小的影响，然后将特异性地在癫痫发作的产生部位充当AED，从而抑制癫痫发作。 癫痫发作而不影响正常的大脑功能。这些研究旨在直接导致临床试验。人类受体和FDA批准的药物的使用应该促进这种从实验室到临床治疗的进步，以便在4年资助结束时，我们将拥有一种基因转移载体，可以考虑用于药物抗性癫痫患者的临床试验。

DESCRIPTION (provided by applicant): Modern drug-discovery research over the last two decades aimed at improving the pharmacological treatment of epileptic seizures has resulted in more than a dozen new anti- epileptic drugs (AEDs). Although these new AEDs may have reduced side effects and drug- drug interactions, the percentage of epileptic patients who continue to have seizures while treated with the new AEDs has remained at 30-40% for >20 years. In this proposal, we aim to develop a gene-therapy approach to treat pharmacoresistant epilepsy through the implementation of a novel "designer" receptor system that should not affect normal brain function, and therefore is less likely to have significant side-effects. This system will utilize adeno-associated viral (AAV) delivery of a modified human ¿1glycine receptor with reduced glycine sensitivity and enhanced sensitivity to the FDA-approved drug, ivermectin. Recombinant AAVs will be genetically optimized for expression in epileptic neurons and tested for efficacy in animal models of epilepsy. Ivermectin, which has minimal effects on the normal brain at the very low concentrations necessary to activate the modified receptor, will then act as an AED specifically at the site of generation of the epileptic seizures, thus suppressing epileptic seizures without affecting normal brain function. These studies are intended to lead directly to clinical trials. The use of a human receptor and an FDA approved drug should facilitate this advancement from bench side to clinical treatment so that by the end of the 4 year grant, we will have a gene transfer vector in hand that could be considered for clinical trials in pharmacoresistant epilepsy patients.