Novel mechanism-based treatments for infantile spasms

基于新机制的婴儿痉挛症治疗方法

• 批准号: 8046718
• 负责人: LIBOR VELISEK
• 金额: $ 6.61万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046718
• 关键词: Achievement; Acute; Address; Adrenal Cortex Hormones; Adverse effects; Agonist; Animal Model; Area; Basic Science; Behavioral; Behavioral Assay; Betamethasone; Brain; Brain region; CRF receptor type 1; Cardiomyopathies; Cessation of life; Child; Childhood; Cognitive; Convulsants; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cost Savings; Cryptogenic West Syndrome; Cushingoid habitus; Defect; Deterioration; Development; Diagnosis; Down-Regulation; Drug usage; Electroencephalography; Electrolytes; Epilepsy; Follow-Up Studies; Gastric ulcer; Growth; Health Care Reform; Hormonal; Human; Hypertension; Hypothalamic structure; Immunosuppression; Impairment; Incidence; Infantile spasms; Intractable Epilepsy; Investigation; Life; Link; Live Birth; Maps; Mediating; Melanocortin 4 Receptor; Mentally Disabled Persons; Metabolic; Methods; Middle Hypothalamus; Modeling; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Obesity; Outcome; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Production; Rattus; Recovery; Research; Science; Scotoma; Seizures; Spasm; Spastic; Structure; Structure of nucleus infundibularis hypothalami; Syndrome; Testing; Therapeutic; Therapeutic Effect; Translating; United States National Institutes of Health; Up-Regulation; Vigabatrin; Work; abstracting; age related; base; comparative efficacy; cost; design; effective therapy; global health; hormone therapy; improved; irritation; mortality; novel; postnatal; premature; prenatal; receptor; response; therapeutic target; tool

DESCRIPTION (provided by applicant): This proposal responding to RFA-OD-10-005, "Recovery Act Limited Competition: NIH Director's Opportunity for Research in Five Thematic Areas (RC4)" fully addresses Research Area 2: Translating Basic Science Discoveries into New and Better Treatments, but also Research Areas 3 (Using Science to Enable Health Care Reform) and 4 (Focusing on Global Health). Infantile spasms (IS) represent a devastating epilepsy syndrome of childhood. IS usually develops between 3-12 months with an incidence of approximately 1 case per 3225 live births. Thus, in the US only there are about 1500 NEW cases of IS, i.e., children who newly require diagnosis and treatment, every year. Worldwide estimate is about 50,000 new patients with IS annually. About 85% of patients with IS become mentally retarded and 67% suffer from intractable epilepsy despite treatment, which is currently mostly hormonal (ACTH, corticosteroids) or vigabatrin, with emergence of new seizure types. IS are associated with significant mortality: about 30% of the patients with IS die mostly during the first 3 years of life. Improvements in therapy of the IS have been severely limited by absence of appropriate animal models for testing new drugs and to study IS mechanisms. Our recently developed model of IS consisting of prenatal priming with betamethasone and postnatal trigger of spasms with NMDA remarkably mimics the human condition: The spastic seizures are age-dependent, associated with EEG electrodecrement and interictal large-amplitude EEG waves, and respond to both acute and long-term treatment with ACTH in a similar way the human IS do. Our follow-up studies revealed several mechanisms that may contribute to the condition of IS: (1) Prenatal priming upregulates expression of melanocortin MC4 receptors in the hypothalamic arcuate nucleus (Arc) one of the brain structures closely linked to the expression of flexion spasms. (2) Prenatal priming upregulates expression of corticotropin releasing factor (CRF) in the Arc. (3) Prenatal priming accelerates developmental switch in replacing NR2B subunit of the NMDA receptor with the NR2A subunit. This proposal will build on these mechanisms to propose three new classes of drug treatment for IS with better efficacy, fewer side effects, and better long-term outcome compared to current IS treatments, with additional substantial cost improvement. Specific aims of this proposal will determine: (1) Activation of MC4 receptors is an effective therapeutic tool against IS. (2) Blockade or downregulation of CRF receptors-1 is effective against IS. (3) Blockade or downregulation of the NR2A subunit of the NMDA receptor will suppress IS. Methods use prenatal priming with betamethasone and postnatal triggering of spasms with NMDA to model IS. Intracranial microinfusions (icv. and intraparenchymal) of specific siRNAs or receptor agonists/antagonists will determine comparative efficacy versus systemic treatment with ACTH or vigabatrin confirmed by EEG/video monitoring. Behavioral assays will evaluate side effects of new treatments and long-term cognitive outcome. PUBLIC HEALTH RELEVANCE: This proposal fully addresses Research Area 2: Translating Basic Science Discoveries into New and Better Treatments, specifically the infantile spasms (IS), which are a devastating epilepsy syndrome of childhood (about 1500 new cases in the USA per year) currently treated either hormonally (ACTH) at tremendous costs or with vigabatrin with significant side effects but neither treatment improves long-term cognitive outcome, thus over 80% of children become mentally retarded. We have developed and validated a model of IS and determined some basic mechanisms that may contribute to the occurrence of IS. Utilizing these mechanistic findings it is proposed to investigate three new classes of drugs and to develop mechanistic IS therapies, which would become superior in efficacy to the current treatment together with fewer side effects and significant improvement in long-term cognitive outcome, and finally would be incomparably cheaper and safer than currently used drugs.

描述（由申请人提供）：本提案响应 RFA-OD-10-005“恢复法案有限竞争：NIH 主任在五个主题领域的研究机会 (RC4)”，全面解决了研究领域 2：将基础科学发现转化为新发现和更好的治疗，还有研究领域 3（利用科学实现医疗保健改革）和 4（关注全球健康）。 婴儿痉挛症 (IS) 是一种破坏性的儿童癫痫综合征。 IS 通常在 3-12 个月内发生，发病率约为每 3225 名活产婴儿 1 例。因此，仅在美国，每年就有约 1500 例新的 IS 病例，即新需要诊断和治疗的儿童。据估计，全球每年约有 50,000 名新的 IS 患者。尽管接受了治疗，但约 85% 的 IS 患者会出现智力迟钝，67% 的患者仍患有难治性癫痫，目前治疗主要是激素（促肾上腺皮质激素、皮质类固醇）或氨己烯酸，并且出现了新的癫痫类型。 IS 与显着的死亡率相关：约 30% 的 IS 患者大多在生命的前 3 年死亡。由于缺乏用于测试新药和研究 IS 机制的适当动物模型，IS 治疗的改进受到严重限制。我们最近开发的 IS 模型包括产前用倍他米松启动和产后用 NMDA 引发痉挛，显着模拟了人类的状况：痉挛性癫痫发作具有年龄依赖性，与脑电图电极衰减和发作间期大振幅脑电图波相关，并对两种急性发作都有反应。以及与人类 IS 类似的长期 ACTH 治疗。我们的后续研究揭示了可能导致 IS 状况的几种机制：(1) 产前启动上调下丘脑弓状核 (Arc) 中黑皮质素 MC4 受体的表达，弓状核是与屈曲痉挛的表达密切相关的大脑结构之一。 (2)产前启动上调弧区促肾上腺皮质激素释放因子(CRF)的表达。 (3) 产前启动加速了用 NR2A 亚基取代 NMDA 受体 NR2B 亚基的发育转换。该提案将建立在这些机制的基础上，提出三类新的 IS 药物治疗方法，与目前的 IS 治疗方法相比，其疗效更好、副作用更少、长期结果更好，并且成本显着改善。 该提案的具体目标将确定：（1）MC4受体的激活是针对IS的有效治疗工具。 (2) 阻断或下调CRF受体-1可有效对抗IS。 (3) 阻断或下调NMDA受体NR2A亚基会抑制IS。方法使用倍他米松产前引发和 NMDA 产后引发痉挛来模拟 IS。特定 siRNA 或受体激动剂/拮抗剂的颅内微量输注（静脉内和实质内）将确定与通过 EEG/视频监测证实的 ACTH 或氨己烯酸全身治疗相比的疗效比较。行为分析将评估新疗法的副作用和长期认知结果。 公共健康相关性：该提案全面涉及研究领域 2：将基础科学发现转化为新的更好的治疗方法，特别是婴儿痉挛症 (IS)，这是一种破坏性的儿童癫痫综合征（美国每年约 1500 个新病例）无论是花费巨大的激素 (ACTH) 治疗，还是副作用显着的氨己烯酸治疗，但这两种治疗都无法改善长期认知结果，因此超过 80% 的儿童出现智力迟钝。我们开发并验证了 IS 模型，并确定了可能导致 IS 发生的一些基本机制。利用这些机制研究结果，建议研究三类新药物并开发机制 IS 疗法，该疗法的疗效将优于当前治疗，同时副作用更少，并且长期认知结果显着改善，最终将是比目前使用的药物更加便宜和安全。