Neurosteroid Treatment for OP Intoxication

描述(申请人提供)：该项目的总体目标是开发一种新型的、广谱的神经类固醇疗法，以减少急性暴露于神经毒剂和有机磷(OP)杀虫剂所造成的发病率和死亡率，这两种杀虫剂对军事和民用人口都是可靠的威胁剂。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。目前用于治疗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，会造成严重的神经元损伤和死亡。我们认为，与苯二氮类药物相比，神经类固醇和增强时相和突触外紧张性抑制的选择性药物对持续性SE具有更有效的保护作用，防止不可逆脑损伤，并延长治疗窗口。这一新的治疗策略是基于神经类固醇新出现的分子机制以及SE所涉及的细胞变化，SE是一种常见的神经毒剂神经毒性。神经类固醇是最有效的抗胆碱能药物所致癫痫发作的药物。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，神经类固醇类药物是治疗OP神经中毒的有效药物。我们有初步证据表明，在匹罗卡品和DFP模型中，晚期暴露后神经类固醇治疗可以迅速控制SE，并在SE后起到神经保护作用，提示神经类固醇治疗具有良好的疗效。本项目的目的是研究合成神经类固醇甘纳索龙及其类似物作为治疗神经毒剂和有机磷农药中毒的广谱药物对策的有效性和安全性。这是我们R21的合理扩展，用于进一步的疗效验证、铅优化和IND应用。主要的重点是生成关于主要候选人的有效性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类药物作为比地西潘更好的对策，我们将解决三个具体目标：(目标1)：确定加纳松龙对DFP和梭曼诱导的SE和脑损伤的疗效；(目标2)：开发经过改进的配方、药代动力学和疗效的加纳松龙类似物，以对抗DFP和梭曼诱导的SE和脑损伤；以及(目标3)：确定加纳松龙或其先导类似物的临床前安全性和毒性，并根据FDA动物规则路径提交IND用于临床开发。该项目将按照循序渐进的“进行/不进行”里程碑计划执行，该计划包括关键研究成功的量化标准，重点放在三个主要结果指标上：(1)抗惊厥效果；(2)神经保护效果；(3)防止神经变性。该项目的成果将确定一种有效的OP中毒解毒剂，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.