DEXTROMETHORPHAN IN RETT SYNDROME

右美沙芬治疗 RETT 综合征

• 批准号: 7378870
• 负责人: SAKKUBAI R NAIDU
• 金额: $ 1.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378870
• 关键词: DEXTROMETHORPHAN; RETT; SYNDROME

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rett syndrome (RTT) is a neurodevelopmental disorder that occurs in 1:10,000-22,000 girls with devastating consequences to brain and systemic neurons. In 70% of individuals having the prescribed clinical features, mutations in the gene encoding for methyl-CpG-binding protein-2 (MeCP2) located on chromosome Xq28 have been identified. MeCP2 is associated with nuclear DNA, and binds to methylated CpG nucleotides, playing a vital role in transcriptional silencing. To date, there is no effective therapy for RTT, and treatment remains palliative. Unfortunately, the brain bears the brunt of the disease during its most vigorous phase of growth, resulting in severe mental retardation. Postmortem brain autoradiographic studies demonstrate a striking and disproportionate increase in the number of glutamate/NMDA (N-methyl-D-aspartate) subtype of receptors in the prefrontal cortex, particularly in younger girls. After the age of 10 years, this dramatic increase in the number of NMDA receptors is reduced to below control values. Furthermore, increased glutamate, but not any other amino acid, has been documented in cerebrospinal fluid (CSF), as well as in brain gray matter by 1H spectroscopic (MRS) studies in RTT patients. The aberrant increase in the excitatory amino acid (EAA) receptors in younger RS patients coincides with the behavioral and epileptic profile, and GI disturbances seen in RTT stages 2 and 3 (18 months-15yrs). Moreover, sudden unexplained death in RTT patients below the age of 15 years is unrelated to seizure frequency and coincides with this period of neuroexcitotoxicity. Commencement of the pathognomonic clinical features in RTT (18 months), with reported increases in EAA glutamate/glycine and NMDA receptors at 2 years, suggests a causal relationship between the onset of autistic-like features, seizures, hand wringing, irritability, and neurotransmitter alterations. The gradual amelioration of symptoms after 15 years of age coincides with a reduction of glutamate/NMDA receptors to below that of control values. Additionally, NMDA receptors that are present in osteoblasts may play a role in the osteopenia seen in RS. It would be important to note if blocking excessive numbers of NMDA receptors in brain and osteoblasts by use of dextromethorphan a competitive blocker of the NMDA receptors could improve spike activity in brain, and bone density. Similar effects could also improve esophageal autonomic dysfunction, measurable by improved motility and reduced reflux. The study will include 90 mutation positive patients. 30 subjects in each age group ranging from <5 years, 5-10 years, and 11-14.99 year will be assigned to each of the 3 treatment arms consisting of 0.25 mg/Kg/day, 2.5 mg/Kg/day, 5 mg/Kg/day in 2 divided doses. As per the FDA guidelines we can only include those patients between 5-14.99 years. Once safety has been established in this age group we will extend the study to those < 5 years, with their approval.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。 RETT综合征（RTT）是一种神经发育障碍，发生在1：10,000-22,000名对脑和系统神经元造成破坏性后果的女孩中。在具有处方临床特征的70％的个体中，已经鉴定了位于XQ28染色体上的甲基-CPG结合蛋白-2（MECP2）的基因中的突变。 MECP2与核DNA有关，并与甲基化的CpG核苷酸结合，在转录沉默中起着至关重要的作用。迄今为止，还没有有效的RTT疗法，并且治疗仍然姑息治疗。不幸的是，在其最剧烈的生长阶段，大脑首当其冲，导致严重的智力低下。尸检后脑自显增生研究表明，谷氨酸/NMDA（N-甲基-D-天冬氨酸）受体中的谷氨酸/NMDA数量的增加和不成比例的增加，尤其是在年轻女孩中。 10岁以后，NMDA受体数量的这种急剧增加减少到控制值以下。此外，在RTT患者中，脑脊液（CSF）以及脑灰质研究中已经记录了谷氨酸盐的增加，但没有其他任何其他氨基酸。年轻RS患者的兴奋性氨基酸（EAA）受体的异常增加与行为和癫痫症状相吻合，在RTT第2阶段和第3阶段（18个月至15岁）中看到的GI障碍。此外，在15岁以下的RTT患者中突然无法解释的死亡与癫痫发作频率无关，并且与这一神经脱毒性时期相吻合。 RTT（18个月）的病理学临床特征的开始，据报道，EAA谷氨酸/甘氨酸和NMDA受体在2年中的增加，这表明自闭症特征的发作，癫痫发作，癫痫发作，手动旋转，烦躁，烦躁和神经递质的变化之间存在因果关系。 15岁后，症状的逐渐改善与将谷氨酸/NMDA受体降低至控制值的降低相吻合。此外，成骨细胞中存在的NMDA受体可能在Rs中看到的骨质减少症中起作用。重要的是要注意，是否通过使用右美甲泛源会阻断大脑中的NMDA受体过量和成骨细胞，而NMDA受体的竞争性阻滞剂可以改善大脑中的尖峰活性和骨密度。类似的作用也可以改善食管自主神经功能障碍，可通过改善运动性和减少反流量来测量。该研究将包括90名突变阳性患者。每个年龄段的30名受试者范围从5年，5-10岁和11-14.99岁的年龄段不等，将分配给由0.25 mg/kg/day，2.5 mg/kg/day，5 mg/kg/day的3个治疗臂中的每个受试者分配给2个分裂剂量。根据FDA指南，我们只能在5 - 1.99年之间包括那些患者。一旦在这个年龄段建立了安全性，我们将在批准的情况下将研究扩展到<5年。