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

系统性寻找 sigma-1 受体配体治疗婴儿痉挛症的新方法

• 批准号: 10216455
• 负责人: LIBOR VELISEK
• 金额: $ 45.1万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216455
• 关键词: Acute; Adrenal Cortex Hormones; Adverse effects; Age; Age-Months; Animal Model; Attention; Behavioral; Betamethasone; Cardiomyopathies; Child; Childhood; Clinical Trials; Cognitive; Corticotropin; Cushingoid habitus; Development; Developmental Delay Disorders; Disease; Electrolytes; Epilepsy; FDA approved; Family; Gastric ulcer; Growth; Hormonal; Human; Hypertension; Hypsarrhythmia; Immunosuppression; Impairment; Infantile spasms; Intractable Epilepsy; Laboratories; Lesion; Ligands; Live Birth; Medical; Modeling; Morbidity - disease rate; N-Methylaspartate; Neurodevelopmental Deficit; Newly Diagnosed; Obesity; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Phase; Pituitary-Adrenal System; Preclinical Testing; Predictive Value; Procedures; Prognosis; Randomized; Rattus; Refractory; Retinal Diseases; Risk; Rodent Model; Scotoma; Seizures; Spasm; Syndrome; System; Testing; Treatment Efficacy; Ulcer; United States National Institutes of Health; Validation; Vigabatrin; Visual Fields; age related; aggressive therapy; behavioral study; cerebral atrophy; comparative efficacy; cost; drug candidate; effective therapy; efficacy evaluation; experience; experimental study; improved; infancy; male; mortality; novel; positive allosteric modulator; postnatal; postnatal development; postnatal period; pre-clinical; prednisolone; prenatal; prospective; randomized trial; response; side effect; sigma receptors; sigma-1 receptor; standard care; symptomatology; tool; white matter

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.

在美国，每年约有1700名儿童在婴儿期被新诊断出患有癫痫痉挛（婴儿 痉挛；是）。在3-12个月大的年龄之间发展，男性占主导地位（60％）。是关联的 具有显着的死亡率和发病率。 IS的医疗选择与其他任何类型的 癫痫。有两种药物具有合理的疗效证据，均由FDA批准：ACTH （肾上腺皮质激素）和Vigabatrin，长期消除了50-55％的患者痉挛。但是，acth 承担巨大的成本负担，在多达43％的案件中，有重大和严重的不利影响，这 包括肥胖，动脉高压，电解质失衡，胃溃疡，生长迟缓，心肌病， 和免疫抑制以及脑萎缩。 Vigabatrin几乎与ACTH短期一样有效，但 一年后的效果滞后。 Vigabatrin由于同心视野缺陷而有很大的风险 周围视网膜病变以不可预测的方式发展。尽管有治疗，但多达85％ 患有IS的患者患有发育消退，后来有67％患有顽固性癫痫。我们确定了 以下差距：在临床前搜索新颖的方法中没有系统的严格方法是治疗方法。 IS的当前治疗方法（即使组合）不足，可能会产生严重的不利影响。大多数 使用ACTH功效的IS缺乏验证的开发模型。 Sigma-1受体配体尚未 检查了针对IS的功效。我们的建议使用经过验证的大鼠模型由产前启动组成 在发育适当的时期内痉挛的产后触发因素。我们模型中的痉挛是 对用ACTH和Vigabatrin敏感。有很好的发作和充 具有IS的模型。还存在延迟的痉挛或癫痫发作，具有延迟的EEG癫痫样活性。模型， 包括ACTH功效在内，已在独立实验室中使用和复制。在这个建议中，我们将 启动对化合物的系统搜索可能有效的IS。我们的初步研究表明 Sigma受体配体（Sigma-1受体变构调节剂）对我们的痉挛具有强大的作用 模型。因此，这类化合物可能会产生新的IS治疗靶标。我们的建议将测试 三层系统中Sigma受体配体之间的治疗候选物。在第1层中，所有潜力 在随机前瞻性试验中，将对治疗化合物进行痉挛的表达测试。在 第2层，这些功效> 50％的药物将被转发到脑电图研究，以调查它们对这两者的影响 急性和延迟的脑电图变化。第3层将调查认知改善，并排除行为 候选药物在第1和2级成功的候选药物产生的不利影响。具体目的是确定 Sigma受体配体在三层阶层中对产前底漆大鼠痉挛的功效。提案将 利用我们的IS啮齿动物模型的独特功能，并至少提供一种前瞻性治疗 在IND研究中，疗效与ACTH相当或更好的候选者且不利影响较少。

项目成果

Astrocyte and Neuronal Panx1 Support Long-Term Reference Memory in Mice.

• DOI: 10.1177/17590914231184712
• 发表时间: 2023-01
• 期刊: ASN NEURO
• 影响因子: 4.7
• 作者: Obot, Price;Subah, Galadu;Schonwald, Antonia;Pan, Jian;Velisek, Libor;Veliskova, Jana;Stanton, Patric K.;Scemes, Eliana
• 通讯作者: Scemes, Eliana