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

基本信息

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
项目类别：
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

项目摘要

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（婴儿期）痉挛；是）。 IS 发生于 3-12 个月大，男性占主导地位 (60%)。 IS 相关具有显着的死亡率和发病率。 IS 的医疗选择不同于任何其他类型的医疗选择癫痫。有两种药物具有合理的疗效证据，均已获得 FDA 批准：ACTH （促肾上腺皮质激素）和氨己烯酸，可长期消除 50-55% 患者的痉挛。然而，ACTH 带来巨大的成本负担，并且在高达 43% 的情况下会产生显着且严重的不利影响，这包括肥胖、高血压、电解质紊乱、胃溃疡、生长迟缓、心肌病、和免疫抑制以及脑萎缩。氨己烯酸短期内几乎与 ACTH 一样有效，但它效果滞后一年。氨己烯酸具有显着的同心视野缺陷风险，因为周围性视网膜病变，其发展方式不可预测。尽管进行了治疗，仍有高达 85% IS患者会出现发育退化，67%的患者随后会患上难治性癫痫。我们确定了存在以下差距：在临床前寻找新型 IS 治疗方法方面没有系统严格的方法。目前的 IS 治疗（即使联合治疗）是不够的，并且可能产生严重的副作用。大部分所开发的 IS 模型缺乏使用 ACTH 功效的验证。 Sigma-1 受体配体尚未被检查了针对 IS 的功效。我们的建议使用经过验证的 IS 大鼠模型，其中包括产前启动以及在发育适当时期产后引发痉挛。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良好的相关性模型与IS。还存在延迟性痉挛或癫痫发作，伴有脑电图癫痫样活动延迟。模型，包括 ACTH 功效，已在独立实验室使用和重现。在本提案中，我们将开始系统地寻找可能有效对抗 IS 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）对我们的痉挛具有强大的作用模型。因此，此类化合物可能会产生 IS 治疗的新靶点。我们的提案将进行测试三层系统中西格玛受体配体中的治疗候选者。在第一层，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。在第 2 级，那些疗效 > 50% 的药物将被转发至脑电图研究，调查其对两者的影响急性和迟发性脑电图改变。第三层将调查认知改善并排除行为改善在第 1 级和第 2 级成功的候选药物所带来的不良反应。具体目标是确定西格玛受体配体对产前引发的大鼠的痉挛的功效分三级。该提案将利用我们的 IS 啮齿动物模型的独特特征并提供至少一种前瞻性治疗候选者的疗效与 ACTH 相当或更好，并且对 IND 研究而言副作用更少。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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