Augmentation of the Cholinergic System in Fragile X Syndrome: A Double-Blind Plac

描述(申请人提供)：脆性X综合征(FRAX)是一种由FMR1基因突变引起的神经发育障碍，是人类认知和行为障碍最常见的可遗传原因。尽管与FRAX有关的研究进展在许多领域都是非同寻常的，但在知识方面仍然存在许多关键差距。特别是，缺乏旨在解决FRAX往往严重的认知和行为症状的治疗方法的信息。与许多其他发育障碍一样，文献中确实存在的FRAX治疗方法的描述主要来自未受控制的案例研究或系列，药物和行为干预针对的是与现象定义的“共病”诊断相关的症状，如AD/HD、自闭症谱系障碍(ASD)或焦虑症。这些情况是次优的，因为这种以症状为基础的治疗对于认知和行为问题的潜在发病机制来说，特异性很低。因此，迫切需要新的研究来开发更有效的、针对FRAX患者的疾病特异性治疗方法。来自我们研究小组和其他人的集中证据有力地支持了功能性胆碱能缺陷导致FRAX认知行为功能障碍的假说。这方面的证据包括：(1)分别用功能MRI和1H-MRS观察到FRAX的胆碱能通路功能和神经化学异常，(2)分析FMR1在人类胚胎发育过程中的胆碱能脑区的高表达，(3)在FRAX的小鼠和苍蝇模型中检测到胆碱能系统异常，(4)分析与胆碱能系统功能现有知识有关的FRAX认知和行为缺陷的具体情况，以及(5)在胆碱酯酶抑制剂多奈哌齐的开放标签试验中观察到12名FRAX患者的认知和行为显著改善。因此，拟议的项目将包括对50名12至21岁的FRAX患者进行多奈哌齐的双盲、安慰剂对照试验。主要的假设是，与安慰剂组相比，服用多奈哌齐的受试者将在行为和认知的特定指标上表现出更大的改善。除了对受FRAX影响的人直接受益外，拟议研究的结果很可能与(目前)特发性发育障碍的亚群高度相关，例如自闭症，这些亚类可能与FRAX具有共同的疾病病理生理机制。这种共同的机制可以通过涉及FMR1蛋白功能的交叉通路发生，或者由于胆碱能功能障碍对认知和行为障碍的贡献相似而发生。 公共卫生相关性：脆性X综合征(FRAX)是人类智力残疾最常见的已知可遗传原因。尽管最近的研究揭示了FRAX的遗传和神经生物学基础，但对受影响个体的特定和有效治疗方法缺乏了解。根据人类和动物研究的信息，FRAX智力残疾的一个原因可能与特定脑神经递质系统(“胆碱能”系统)的缺陷有关。因此，我们建议使用一种特定的药物多奈哌齐来增强受FRAX影响的青少年的胆碱能系统。如果被发现是有效的，这项研究产生的知识也可能与其他与FRAX共享共同疾病途径的发育障碍相关。

DESCRIPTION (provided by applicant): Fragile X syndrome (FraX), a neurodevelopmental disorder caused by mutations of the FMR1 gene, is the most common known heritable cause of cognitive and behavioral disability in humans. Though research progress pertaining to FraX has been extraordinary in many areas, many critical gaps in knowledge remain. In particular, there is a dearth of information on treatments designed to address the often-serious cognitive and behavioral symptoms of FraX. Like many other developmental disorders, descriptions of treatments for FraX that do exist in the literature are primarily derived from uncontrolled case studies or series, with both pharmacological and behavioral interventions targeted to symptoms associated with phenomenologically defined "co-morbid" diagnoses such as AD/HD, autism spectrum disorders (ASD) or anxiety disorders. These circumstances are suboptimal as such symptom-based treatments represent a low level of specificity with respect to the underlying pathogenesis of cognitive and behavioral problems. Accordingly, new research to develop more effective, disease-specific treatments for persons with FraX is greatly needed. Converging evidence from our research group and others strongly support a hypothesis of functional cholinergic deficits contributing to cognitive-behavioral dysfunction in FraX. This evidence includes: (1) abnormalities of cholinergic pathway function and neurochemistry observed with functional MRI and 1H-MRS, respectively, in FraX, (2) an analysis of FMR1 expression during human fetal development indicating particularly high expression in cholinergic brain regions, (3) cholinergic system abnormalities detected in the mouse and fly models of FraX, (4) an analysis of the specific profile of cognitive and behavioral deficits in FraX in relation to current knowledge of cholinergic system functions, and, (5) significant improvements in cognition and behavior observed in 12 individuals with FraX during an open-label trial of donepezil, a cholinesterase inhibitor. Accordingly, the proposed project will consist of a double blind, placebo controlled trial of donepezil in 50 individuals with FraX, ages 12 to 21 years. The primary hypothesis is that subjects receiving donepezil will show greater improvements in specific measures of behavior and cognition, relative to the placebo group. In addition to direct benefit to persons affected by FraX, findings from the proposed research are likely to be highly relevant to subgroups of (currently) idiopathic developmental disorders, such as autism, that might share common pathophysiological mechanisms of disease with FraX. Such shared mechanisms could occur through intersecting pathways involving FMR1 protein function or as a result of similarities in the contribution of cholinergic dysfunction to cognitive and behavioral disability. PUBLIC HEALTH RELEVANCE: Fragile X syndrome (FraX) is the most common known heritable cause of human intellectual disability. Though recent research has revealed much about the genetic and neurobiological bases of FraX, knowledge about specific and effective treatments for affected individuals is lacking. Based on information from both human and animal studies, one cause of intellectual disability in FraX may be related to deficits in a particular brain neurotransmitter system (the "cholinergic" system). Thus, we propose to use a specific medication, donepezil, to augment cholinergic system in adolescents affected by FraX. If found to be effective, the knowledge generated by this research may also be relevant to other developmental disorders that share common disease pathways with FraX.