Novel mechanism-based treatments for infantile spasms

描述（由申请人提供）：该提案响应RFA-OD-10-005，“恢复法案有限竞争：NIH主任在五个主题领域（RC4）的研究机会”，全面解决研究领域2：将基础科学发现转化为新的更好的治疗方法，以及研究领域3（利用科学促进医疗改革）和4（关注全球健康）。婴儿痉挛（IS）是儿童时期一种毁灭性的癫痫综合征。IS通常在3-12个月间发病，发病率约为每3225例活产1例。因此，仅在美国，每年就有大约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5万名is新患者。大约85%的IS患者出现智力迟钝，67%的患者尽管接受了治疗，但仍患有顽固性癫痫，目前治疗主要是激素（促肾上腺皮质激素、皮质类固醇）或维加巴林，并出现了新的癫痫发作类型。IS与显著的死亡率相关：大约30%的IS患者大多在生命的前3年死亡。由于缺乏适当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模型包括产前用倍他米松启动和产后用NMDA触发痉挛，这明显模仿了人类的情况：痉挛发作是年龄依赖性的，与脑电图电衰减和间隔大振幅脑电波有关，并且对ACTH的急性和长期治疗的反应与人类IS相似。我们的后续研究揭示了可能导致IS的几种机制：(1)产前启动上调下丘脑弓状核（Arc）中黑素皮质素MC4受体的表达，这是与屈曲痉挛表达密切相关的大脑结构之一。(2)产前启动可上调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NR2B亚基被NR2A亚基取代的发育开关。该提案将以这些机制为基础，提出三种新的IS药物治疗方法，与目前的IS治疗方法相比，它们具有更好的疗效、更少的副作用和更好的长期疗效，同时还能大幅降低成本。本提案的具体目标将确定：(1)MC4受体的激活是对抗is的有效治疗工具。(2)阻断或下调CRF受体-1对is有效。(3)阻断或下调NMDA受体NR2A亚基可抑制IS。方法采用产前用倍他米松启动和产后用NMDA触发痉挛来模拟IS。颅内微输液（icv）（脑实质内）特异性sirna或受体激动剂/拮抗剂将决定与经脑电图/视频监测证实的ACTH或维加巴林全身治疗相比的比较疗效。行为分析将评估新疗法的副作用和长期认知结果。

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.