Novel mechanism-based treatments for infantile spasms

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（RC 4）的研究机会”，充分解决了研究领域2：将基础科学发现转化为新的和更好的治疗方法，以及研究领域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（IS）是儿童期的一种毁灭性癫痫综合征。IS通常在3-12个月之间发展，发病率约为每3225例活产1例。因此，仅在美国就有大约1500例新的IS病例，即，每年都有新的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。大约85%的IS患者变得智力迟钝，67%的患者尽管接受了治疗，但仍患有顽固性癫痫，目前主要是激素（ACTH，皮质类固醇）或氨己烯酸，并出现了新的癫痫发作类型。IS与显著的死亡率相关：约30%的IS患者大多在生命的前3年死亡。由于缺乏合适的动物模型来测试新药和研究IS机制，IS治疗的改进受到严重限制。我们最近开发的IS模型包括产前启动与betterazole和产后触发的痉挛与NMDA显着模仿人类的条件：痉挛性癫痫发作是年龄依赖性的，与EEG电减量和发作间期大振幅EEG波，并响应于急性和长期治疗与ACTH以类似的方式，人类IS。我们的后续研究揭示了几种可能导致IS的机制：（1）产前启动上调下丘脑弓状核（Arc）中黑皮质素MC 4受体的表达，该脑结构与屈曲痉挛的表达密切相关。(2)产前预激上调Arc中促肾上腺皮质激素释放因子（CRF）的表达。(3)产前启动加速了NMDA受体NR 2A亚基取代NR 2B亚基的发育转换。该提案将建立在这些机制的基础上，提出三种新的IS药物治疗，与目前的IS治疗相比，具有更好的疗效，更少的副作用和更好的长期结果，并具有额外的大幅成本改善。 本提案的具体目标将确定：（1）激活MC 4受体是一种有效的治疗工具，对IS。(2)阻断或下调CRF受体-1对IS有效。(3)阻断或下调NMDA受体的NR 2A亚单位将抑制IS。方法采用出生前用β-内酰胺酶预激和出生后用NMDA诱发痉挛的方法建立IS模型。颅内微量输注（icv.和脑实质内）的特异性siRNA或受体激动剂/拮抗剂将确定与通过EEG/视频监测确认的ACTH或氨己烯酸的全身治疗相比的比较功效。行为分析将评估新治疗的副作用和长期认知结果。 公共卫生相关性：该提案充分解决了研究领域2：将基础科学发现转化为新的更好的治疗方法，特别是婴儿痉挛症（IS），这是一种毁灭性的儿童癫痫综合征（美国每年约有1500例新病例），目前要么以巨大的成本接受垂体促肾上腺皮质激素（ACTH）治疗，要么接受氨己烯酸治疗，副作用显著，但两种治疗都不能改善长期认知结果，因此超过80%的儿童智力迟钝。我们已经开发和验证了一个模型，IS和确定一些基本的机制，可能有助于发生IS。利用这些机制的研究结果，它提出了三个新的类别的药物和开发机制的IS疗法，这将成为上级的疗效优于目前的治疗，以及更少的副作用和显着改善长期的认知结果，并最终将是无与伦比的便宜和安全比目前使用的药物。

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.