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）：对RFA-OD-10-005做出响应的该提案，“恢复法竞争：NIH导演在五个主题领域的研究机会（RC4）”完全解决了研究区域2：将基础科学发现转化为新的，更好的治疗方法，但也将研究领域转化为3（使用科学医疗保健改革）和4（重点是全球健康）。 婴儿痉挛（IS）代表了儿童时期毁灭性癫痫综合征。通常在3-12个月之间发育，每3225例活产的发生率约为1例。因此，在美国，每年都有大约1500例IS的新病例，即新需要诊断和治疗的孩子。全球估计每年约有50,000名新患者。大约85％的患者患有智障患者，尽管治疗治疗，但有67％的患者患有顽固性癫痫，目前主要是激素（ACTH，皮质类固醇）或Vigabatrin，并出现了新的癫痫发作类型。与重大死亡率有关：约有30％的患者在生命的头三年中死亡。由于缺乏适当的动物模型来测试新药和研究是机制，因此对IS治疗的改善受到了严重限制。我们最近开发的模型是由替米塞松的产前启动和NMDA的痉挛产后触发触发，非常模仿人类的状况：痉挛性癫痫发作是年龄依赖性的，与EEG电位和间隔振兴和大型振幅EEG EEG ee ee，并对Acth的急性和长期治疗均与人类相似的方式响应。我们的后续研究揭示了几种可能导致IS条件的机制：（1）产前启动的上调在下丘脑弧形核核（ARC）中，黑色素性素MC4受体的表达是与屈曲痉挛表达紧密相关的大脑结构之一。 （2）产前启动的启动会上调ARC中皮质激素释放因子（CRF）的表达。 （3）用NR2A亚基代替NMDA受体的NR2B亚基，可以加速发育开关。该提议将基于这些机制，以提出三种新的药物治疗类别的IS，具有更好的功效，更少的副作用和与当前治疗相比的长期结局更好的长期结局，并进行了更大的成本提高。 该提案的具体目的将确定：（1）激活MC4受体是对IS的有效治疗工具。 （2）CRF受体-1的阻断或下调是有效的。 （3）NMDA受体的NR2A亚基的阻塞或下调将抑制。方法将产前启动与替他塞米松一起使用，并使用NMDA的痉挛发生后的痉挛触发。特定的siRNA或受体激动剂/拮抗剂的颅内微炎（ICV和核内充质）将确定通过EEG/视频监测证实的ACTH或Vigabatrin的比较疗效与全身治疗。行为分析将评估新疗法和长期认知结果的副作用。 公共卫生相关性：该提案完全解决了研究领域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（IS），这是一种毁灭性的儿童时期癫痫综合征（每年约1500例新病例）（目前约有1500例新病例），目前既不在繁荣的范围内均可促进了既定的副作用，又不适用于促进的副作用，既不是均等效果，又不效果。精神智障。我们已经开发并验证了一个IS的模型并确定了一些可能有助于IS发生的基本机制。利用这些机械性发现，提议研究三种新的药物并开发机械性的是疗法，这将在疗效中与当前治疗相同，并且长期认知结果的副作用较少，最终将是比当前使用的药物更便宜和更安全的。