Neurosteroid Treatment for OP Intoxication

描述（由申请人提供）：该项目的总体目标是开发一种新的，广谱的神经类固醇治疗，将减轻急性暴露于神经毒剂和有机磷农药（OP），这是可信的威胁剂为军事和平民人口所造成的发病率和死亡率。暴露于神经毒剂或OP中毒可导致持续性癫痫发作、癫痫持续状态（SE）和永久性脑损伤。目前用于神经中毒的抗惊厥药物（苯二氮卓类）不能充分保护大脑免受SE的影响，SE是一种持续30分钟或更长时间的癫痫发作活动，具有显著的神经元损伤和死亡率。我们建议，神经甾体和选择性药物，提高阶段性和突触外紧张性抑制产生更有效的保护持续性SE比苯二氮卓类药物，防止不可逆的脑损伤，并延长治疗窗口。这种新的治疗策略是基于神经类固醇的新兴分子机制以及SE（神经毒剂的常见神经毒性）中涉及的细胞变化。神经甾体类药物是对抗胆碱能药物诱发癫痫发作最有效的抗惊厥药物。由于OP神经毒剂通过胆碱能过度激活引起持续性癫痫发作和脑损伤，因此建议神经类固醇是比苯二氮卓类更有效的OP神经中毒抗惊厥药。我们有初步证据表明，晚期暴露后神经类固醇治疗可以快速控制SE，并在毛果芸香碱和DFP模型中SE后具有神经保护作用，表明神经类固醇治疗的有效性。本项目的目的是调查合成神经类固醇加奈索酮及其类似物作为神经毒剂和OP农药中毒的“广谱”医疗对策的有效性和安全性。这是我们R21的逻辑扩展，用于进一步的有效性验证、电极导线优化和IND申请。主要重点是生成关于主要候选药物疗效和安全性的必要数据，并在5年内提交IND申请。为了开发神经类固醇作为比地西泮更优越的上级对策，我们将致力于三个具体目标：（目标1）：确定加奈索酮对DFP和梭曼诱导的SE和脑损伤的功效;（目标2）：开发具有改善的制剂药代动力学和对DFP和梭曼诱导的SE和脑损伤的功效的加奈索酮类似物;以及（目标3）：确定加奈索酮或其主要类似物的临床前安全性和毒性，并根据FDA动物规则途径提交IND进行临床开发。该项目将按照渐进的“进行/不进行”里程碑计划实施，其中包括重点关注三个主要结局指标的关键研究成功的定量标准：（i）抗惊厥疗效;（ii）神经保护剂疗效;和（iii）预防神经变性。该项目的成果将确定OP中毒的有效解毒剂，并加强对紧急情况的准备。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a novel, broad-spectrum neurosteroid therapy that will mitigate the morbidity and mortality caused by acute exposure to nerve agents and organophosphate (OP) pesticides, which are credible threat agents for military and civilian populations. Exposure to nerve agents or OP poisoning can result in persistent seizures, status epilepticus (SE), and permanent brain injury. Current anticonvulsant countermeasures (benzodiazepines) for nerve intoxication do not sufficiently protect the brain from SE, a prolonged seizure activity lasting 30 min or longer with significant neuronal injury and mortality. We propose that neurosteroids and selective drugs that enhance phasic and extrasynaptic tonic inhibition produce more effective protection against persistent SE than benzodiazepines, prevent irreversible brain injury, and extend the therapeutic window. This novel therapeutic strategy is based on the emerging molecular mechanisms of neurosteroids and also cellular changes involved in SE, a common neurotoxicity by nerve agents. Neurosteroids are the most powerful anticonvulsants against seizures induced by cholinergic agents. Since OP nerve agents cause persistent seizures and brain damage through cholinergic hyperactivation, it is proposed that neurosteroids are more effective anticonvulsants for OP nerve intoxication than benzodiazepines. We have pilot evidence that late post-exposure neurosteroid therapy can rapidly control SE and be neuroprotective after SE in pilocarpine and DFP models, suggesting the promising efficacy of neurosteroid therapy. The objective of this project is to investigate the efficacy and safety of the synthetic neurosteroid ganaxolone and its analogs as 'broad-spectrum' medical countermeasures for nerve agent and OP pesticide intoxication. This is a logical extension of our R21s for further efficacy validation, lead optimization, and IND application. The primary emphasis is to generate requisite data on the efficacy and safety of the lead candidate and submit an IND application within a 5 year period. To develop neurosteroids as superior countermeasures than diazepam, we will address three specific aims: (Aim 1): Determine the efficacy of ganaxolone against DFP- and soman-induced SE and brain damage; (Aim 2): Develop ganaxolone analogs with improved formulation pharmacokinetics and efficacy against DFP- and soman-induced SE and brain damage; and (Aim 3): Determine the preclinical safety and toxicity of ganaxolone or its lead analog and submit an IND for clinical development under the FDA Animal Rule Pathway. The project will be implemented as per the progressive "go/no-go" milestones plan, which includes quantitative criteria for the success of key studies focusing on three primary outcome measures: (i) anticonvulsant efficacy; (ii) neuroprotectant efficacy; and (iii) prevention of neurodegeneration. The outcome from this project will identify an effective antidote for OP intoxication and enhance readiness for emergencies.