Ph 2 Study of Dextromethorphan in the Treatment of Rett Syndrome

项目概要/摘要： 我们的建议包括一项“安慰剂对照试验的美沙芬在雷特综合征”， 在肯尼迪克里格研究所（KKI）/约翰霍普金斯医疗机构（JHMI）进行。 RTT是一种神经发育障碍，对大脑和 系统神经元患有RTT的女孩有癫痫发作和多动运动， 过度的兴奋性神经元活动，以及兴奋性神经递质的水平， 脑脊液中谷氨酸的含量升高脑磁共振波谱（MRS） 也显示出高水平的谷氨酸盐死后额叶神经递质放射自显影 来自8岁以下女孩的RTT皮质显示NMDA型显著增加， （N-甲基-D-天冬氨酸）谷氨酸受体，尽管其数量减少了50%， 突触此外，我们在体外研究了来自具有突变的小鼠的培养神经元， MECP 2基因对缺氧和谷氨酸介导的细胞凋亡异常敏感 兴奋性毒性对这些小鼠的电生理学研究表明， 海马和皮层节律性放电。由于DM竞争性阻断NMDA 受体通道，我们建议，它将改善RTT的临床表现（异常 行为、认知缺陷、神经生理异常和癫痫发作）， 兴奋性突触活动，从而拯救脑组织免受兴奋性毒性。目前，RTT已 无法治愈我们的目的是测试糖尿病在RTT中的有效性和安全性，以改善沟通 减轻行为和身体症状。为实现这一目标，成果措施是： 主要结局：马伦的接受语言年龄等效评分改善 量表;次要结局：a）马伦量表其他子量表的改善; B）改善 在Vineland适应行为的社会化和沟通量表中; c）改善 在Ghuman-Folstein的社交互动屏幕上。探索性变量为a） 异常行为检查表评分; B）Rett综合征行为问卷; c）EEG和 不匹配阴性; d）生活质量问卷。总共有60名受试者谁是快 具有RTT临床特征和已知MECP 2基因突变的DM代谢者， 在一项双盲试验中，随机分配至安慰剂组或5 mg 使用区组和分层（针对年龄和年龄）， 癫痫发作的存在）随机化。将在意向治疗基础上进行分析。我们 先前的研究表明，提高警觉性和社会互动的神经心理和 行为评估结果令人鼓舞

Project Summary/Abstract: Our proposal consists of a "Placebo controlled trial of dextromethorphan in Rett syndrome" to be conducted at the Kennedy Krieger Institute (KKI)/Johns Hopkins Medical Institutions (JHMI). RTT is a neurodevelopmental disorder with devastating consequences on both brain and systemic neurons. Girls with RTT have seizures and hyperkinetic movements suggesting excessive excitatory neuronal activity, and the levels of the excitatory neurotransmitter, glutamate, in cerebrospinal fluid are elevated. Brain magnetic resonance spectroscopy (MRS) also shows high levels of glutamate. Neurotransmitter autoradiography of postmortem frontal cortex from girls less than 8 years of age with RTT showed a significant increase in NMDA-type (N-methyl-D-aspartate) glutamate receptors despite a 50% reduction in the number of synapses. Additionally, our in vitro studies of cultured neurons from mice with a mutation in the MECP2 gene show that they are abnormally sensitive to hypoxia and glutamate mediated excitotoxicity. Electrophysiologic studies of these mice show enhanced excitability in the hippocampus and rhythmic discharges in cortex on EEG. As DM competitively blocks NMDA receptor channels, we propose that it will improve the clinical manifestations of RTT (abnormal behaviors, cognitive deficits, neurophysiological abnormalities, and seizures) by reducing excitatory synaptic activity thereby rescuing brain tissue from excitotoxicity. Presently, RTT has no cure. Our objective is to test the efficacy and safety of DM in RTT to improve communication and alleviate behavioral and physical symptoms. Towards this goal, the outcome measures are: Primary outcome: Improvement in the receptive language age equivalent scores on the Mullen scale; Secondary outcomes: a) Improvement in other subscales of the Mullen; b) Improvement in the Socialization and Communication scales of Vineland Adaptive Behavior; c) Improvement in the Ghuman- Folstein Screen for Social Interaction. Exploratory variables are a) Change in the Aberrant Behavior Checklist scores; b) Rett Syndrome Behavior Questionnaire; c) EEG and MisMatch Negativity; d) Quality of Life Questionnaire. A total of 60 subjects who are fast metabolizers of DM, with clinical features of RTT and a known mutation in the MECP2 gene, will be equally randomized in a double-masked trial to placebo or treatment with 5mg dextromethorphan /kg/day for twelve weeks using a blocked and stratified (for age and the presence of seizures) randomization. Analyses will be done on an intention-to-treat basis. Our previous study showing improved alertness and social interaction on neuropsychological and behavioral assessments is encouraging.