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，现代药物发现研究旨在改善癫痫发作的药理学治疗，已经产生了十多种新的抗癫痫药物（aed）。尽管这些新型抗癫痫药可能减少了副作用和药物-药物相互作用，但在使用新型抗癫痫药治疗期间癫痫患者继续发作的百分比在20至20年间一直保持在30-40%。在这个提议中，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”受体系统来治疗耐药癫痫，这种系统不应该影响正常的大脑功能，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）递送修饰的人甘氨酸受体，降低甘氨酸敏感性，增强对fda批准的药物伊维菌素的敏感性。重组aav将在癫痫神经元中进行基因优化表达，并在癫痫动物模型中测试其有效性。伊维菌素对正常大脑的影响很小，其浓度非常低，无法激活修饰的受体，随后将在癫痫发作的产生部位起到AED的作用，从而抑制癫痫发作

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.