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）被新诊断出患有癫痫痉挛 痉挛; IS）。IS发生在3-12个月龄之间，男性占优势（60%）。IS与 死亡率和发病率都很高。IS的医疗选择不同于任何其他类型的疾病。 癫痫有两种药物具有合理的疗效证据，均已获得FDA批准： （促肾上腺皮质激素）和氨己烯酸，长期消除50-55%患者的痉挛。然而，ACTH 具有巨大的成本负担，并且在高达43%的情况下具有显著和严重的不良影响， 包括肥胖、动脉高血压、电解质失衡、胃溃疡、生长迟缓、心肌病 以及免疫抑制和脑萎缩。氨己烯酸几乎是一样有效的促肾上腺皮质激素短期，但它 在一年后生效。氨己烯酸具有显著的向心性视野缺损的风险， 外周视网膜病变，其以不可预测的方式发展。尽管有治疗，高达85%的 IS患者有发育性退化，67%的患者后来患有难治性癫痫。我们确定 以下差距：没有系统的严格的方法在临床前搜索新的IS治疗。 目前IS的治疗（即使联合治疗）不足，可能会产生严重的不良反应。大部分 所开发的IS模型缺乏使用ACTH功效的验证。Sigma-1受体配体尚未被发现。 检查对IS的有效性。我们的建议是使用一个有效的大鼠模型IS组成的产前引发 和出生后在发育适当时期引发痉挛。我们模型中的痉挛是 对ACTH和氨己烯酸治疗敏感。发作期和发作间期脑电图与此有很好的相关性 模型与IS也有迟发性痉挛或癫痫发作伴迟发性EEG癫痫样活动。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 启动对可能有效对抗IS的化合物的系统搜索。我们的初步研究表明， σ受体配体（σ-1受体变构调节剂）在我们的研究中对痉挛具有强大的作用， 模型因此，这类化合物可能产生新的IS治疗靶点。我们的提议将检验 三层系统中σ受体配体中的治疗候选物。在第1层，所有潜在的 将在随机前瞻性试验中针对痉挛的表现测试治疗化合物。在 第2层，疗效>50%的药物将被转发到EEG研究，研究其对两种药物的影响。 急性和迟发性EEG改变。第3层将调查认知改善以及排除行为 在第1层和第2层中成功的候选药物产生的不良反应。具体目标是确定 σ受体配体对产前致敏大鼠痉挛的三个层次的功效。该提案将 利用我们的IS啮齿动物模型的独特功能，并提供至少一种前瞻性治疗 候选人具有与ACTH相当或更好的疗效，并且对于IND研究具有更少的不良反应。

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.