Systematic search for novel treatments of infantile spasms among sigma-1 receptor ligands

在美国，每年约有1700名儿童在婴儿期(婴儿期)新诊断为癫痫痉挛 痉挛；是)。是在3-12个月龄之间发育的，男性占优势(60%)。IS关联 死亡率和发病率都很高。IS的医疗选择与任何其他类型的IS不同 癫痫。有两种药物有合理的疗效证据，都得到了FDA的批准：ACTH (促肾上腺皮质激素)和Vigabatrin，可长期消除50%-55%的患者的痉挛。然而，ACTH 带来巨大的成本负担，在高达43%的情况下会产生重大和严重的不利影响， 包括肥胖、动脉高血压、电解质失衡、胃溃疡、生长迟缓、心肌病 免疫抑制和脑萎缩。Vigabatrin短期内几乎和ACTH一样有效，但它 一年后，效果会滞后。Vigabatrin有很大的同心性视野缺陷的风险，因为 周围性视网膜病变，以一种不可预测的方式发展。尽管接受了治疗，高达85%的 IS患者有发育衰退，67%的患者后来患上顽固性癫痫。我们确认了 以下差距：在临床前寻找新的IS治疗方法方面没有系统的严格方法。 目前对IS的治疗(即使是联合治疗)是不够的，可能会产生严重的不良影响。大部分 所开发的IS模型缺乏使用ACTH有效性的验证。Sigma-1受体配体尚未被 检查对IS的有效性。我们的方案使用了一种经过验证的IS大鼠模型，该模型包括产前启动 以及发育适宜期痉挛的产后触发。我们模型中的痉挛是 对ACTH和Vigabatrin治疗敏感。发作期和发作间期脑电有很好的相关性。 与IS一起做模特。也有延迟性痉挛或癫痫发作，脑电癫痫样活动延迟。这个模型， 包括促肾上腺皮质激素的功效，已经在独立的实验室中使用和复制。在本提案中，我们将 启动系统研究，寻找可能对IS有效的化合物。我们的初步研究表明 Sigma受体配体(Sigma-1受体变构调节剂)具有强大的抗痉挛作用。 模特。因此，这类化合物可能会产生治疗IS的新靶点。我们的提案将检验 Sigma受体配体在三级系统中的治疗候选。在第1层，所有潜力 治疗化合物将在随机前瞻性试验中针对痉挛的表现进行测试。在……里面 第二级，那些有效率为50%的药物将被提交给EEG研究，调查它们对两者的影响 急性和延迟性脑电改变。第三级将调查认知方面的改进并排除行为方面的改进 1级和2级成功的候选药物所产生的不良反应。具体目的是确定 Sigma受体配体对产前预激大鼠三级痉挛的疗效。这项提议将 利用我们的IS啮齿动物模型的独特功能，提供至少一种前瞻性治疗 IND研究中疗效与ACTH相当或优于ACTH且不良反应较少的候选人。

Every year in the US ~1700 children are newly diagnosed with epileptic spasms during infancy (infantile spasms; IS). IS develop between 3-12 months of age with a predominance (60%) in males. IS are associated with significant mortality and morbidity. Medical treatment options for IS are different than for any other types of epilepsy. There are two drugs with a reasonable evidence of efficacy, both approved by FDA: ACTH (adrenocorticotropin) and vigabatrin, eliminating spasms in 50-55% of patients in long term. However, ACTH carries enormous cost burden and, in up to 43% of cases has significant and serious adverse effects, which include obesity, arterial hypertension, electrolyte imbalance, gastric ulcer, growth retardation, cardiomyopathy, and immunosuppression as well as brain atrophy. Vigabatrin is almost as effective as ACTH short-term but it lags in effects after one year. Vigabatrin has a significant risk for concentric visual field deficits due to peripheral retinopathy, which develops in an unpredictable manner. Despite the treatments, up to 85% of patients with IS have developmental regression and 67% suffer from intractable epilepsy later. We identified the following gaps: There is no systematic rigorous approach in the preclinical search for novel IS treatments. Current treatments of IS (even if in combination) are insufficient and may have serious adverse effects. Most of the developed models of IS lack validation using the ACTH efficacy. Sigma-1 receptor ligands have not been examined for efficacy against IS. Our proposal uses a validated rat model of IS consisting of prenatal priming and postnatal trigger of spasms during developmentally appropriate period. The spasms in our model are sensitive to treatment with ACTH as well as vigabatrin. There is good ictal and interictal EEG correlate of this model with IS. There are also delayed spasms or seizures with delayed EEG epileptiform activity. The model, including ACTH efficacy, has been used and reproduced in independent laboratories. In this proposal we will initiate systematic search for compounds potentially effective against IS. Our preliminary studies show that sigma receptor ligands (sigma-1 receptor allosteric modulators) have robust effects against the spasms in our model. Therefore, this class of compounds may produce novel targets for IS treatment. Our proposal will test the treatment candidates among sigma receptor ligands in the three-tier system. In Tier 1, all potential treatment compounds will be tested against the expression of spasms in the randomized prospective trial. In Tier 2, those drugs with >50% efficacy will be forwarded to the EEG study investigating their effects on both acute and delayed EEG changes. Tier 3 will investigate cognitive improvements as well as rule out behavioral adverse effects afforded by the candidate drugs successful in Tiers 1 and 2. Specific aim is to determine efficacy of sigma receptor ligands against the spasms in prenatally primed rats in three tiers. The proposal will take advantage of unique features of our rodent model of IS and deliver at least one prospective treatment candidate with efficacy comparable to or better than ACTH and with fewer adverse effects for an IND study.