Ivermectin and human glycine receptor suppression of pharmacoresistant epilepsy

伊维菌素和人甘氨酸受体抑制耐药性癫痫

• 批准号: 8471216
• 负责人: F. Edward DUDEK
• 金额: $ 30.19万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471216
• 关键词: Acute; Adverse drug effect; Adverse effects; Affect; Affinity; Animal Model; Antiepileptic Agents; Brain; Clinical Treatment; Clinical Trials; Development; Drug Interactions; Eligibility Determination; Engineering; Epilepsy; FDA approved; Gene Expression; Gene Targeting; Generations; Genetic; Glycine; Glycine Receptors; Grant; Hand; Human; In Vitro; Ivermectin; Lead; Ligands; Modeling; Molecular; Monitor; Neurons; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Receptor Gene; Recombinants; Research; Seizures; Side; Site; Specificity; System; Techniques; Testing; Transgenic Mice; Viral; Viral Genes; Viral Vector; Wireless Technology; base; drug discovery; efficacy testing; experience; gene therapy; gene transfer vector; improved; in vivo; nervous system disorder; novel; receptor; research study; tool

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.

描述（由申请人提供）：过去二十年旨在改善癫痫发作的药物治疗的现代药物发现研究已经产生了十多种新的抗癫痫药物（AED）。尽管这些新型 AED 可能减少了副作用和药物间相互作用，但在使用新型 AED 治疗期间癫痫患者持续癫痫发作的比例在超过 20 年的时间里一直保持在 30-40%。在这项提案中，我们的目标是开发一种基因治疗方法，通过实施一种新型“设计”受体系统来治疗耐药性癫痫，该系统不会影响正常的大脑功能，因此不太可能产生显着的副作用。该系统将利用腺相关病毒 (AAV) 传递修饰的人类 ¿1 甘氨酸受体，降低甘氨酸敏感性并增强对 FDA 批准的药物伊维菌素的敏感性。重组 AAV 将针对在癫痫神经元中的表达进行基因优化，并在癫痫动物模型中测试其功效。伊维菌素在激活修饰受体所需的极低浓度下对正常大脑的影响很小，然后将专门针对癫痫发作的部位充当 AED，从而抑制癫痫发作 癫痫发作不影响正常的大脑功能。这些研究旨在直接进行临床试验。使用人类受体和 FDA 批准的药物应该会促进从临床治疗到临床治疗的进展，以便在 4 年资助结束时，我们将拥有一个基因转移载体，可以考虑在耐药性癫痫患者中进行临床试验。