Multi-modal Treatment of Fragile X Syndrome: From Cell to Child

加州大学戴维斯分校MIND研究所IDDRC提出了一个与多模态相关的研究项目 治疗方法的主题，跨越基础和临床科学，并利用五个拟议的核心。 脆性X综合征（FXS）神经生物学的最新进展已经导致了靶向治疗， FMRI敲除（KO）小鼠和其它动物模型中的许多表型特征（Berry-Kravis等， 2011; Bhakar等人，2012; Hagerman等人，2012年）。这些治疗中的许多都是基于mGluRS （代谢型谷氨酸受体5）的FXS的理论，提出了FMRP的缺乏或减少， 完全突变导致mGluRS通路对谷氨酸的超敏反应，这导致智力低下。 损伤、癫痫发作和FXS的其它特征（Bear等人，2004; Dolen等人，2007; Huber等人，二○ ○二年; Osterweil等人，2010年）。事实上，mGluRS拮抗剂已被证明在挽救几种FXS相关的 啮齿动物的表型（Dolen等人，2010年）。与动物研究相反， mGluRS在人类中仅显示出适度的功效（Berry-Kravis等人，2012年）。三个因素促成了 人类研究结果，（a）FXS中有多种途径受到影响;因此，仅针对单一途径不太可能 完全纠正复杂的表型。必须确定额外的靶标，以便使多药制剂 （B）许多临床试验中使用的结局指标不足以 检测细微但有意义的治疗效果。(3)重要的治疗诱导的脑功能变化 可能只会在FXS患者的可观察行为中产生适度的短期变化， 治疗前错过和非规范学习机会的历史。然而，有可能 通过增加行为干预来“增强”药物的表型效应， 大脑功能

The UC Davis MIND Institute IDDRC proposes a Research Project relevant to the Multi-modal Treatment Approaches theme that spans basic and clinical science and utilizes five of the proposed cores. Recent advances in the neurobiology of fragile X syndrome (FXS) have led to targeted treatments that rescue many phenotypic features in the FMRI knock out (KO) mouse and other animal models (Berry-Kravis et al., 2011; Bhakar et al., 2012; Hagerman et al., 2012). Many of these treatments are based on the mGluRS (metabotropic glutamate receptor 5) theory of FXS, which proposes that absence or reduction of FMRP in the full mutation leads to hypersensitivity of the mGluRS pathway to glutamate, which causes intellectual impairments, seizures, and other features of FXS (Bear et al., 2004; Dolen et al., 2007; Huber et al., 2002; Osterweil et al., 2010). In fact, mGluRS antagonists have proven effective in rescuing several FXS-related phenotypes in rodents (Dolen et al., 2010). In contrast to animal studies, therapeutic approaches targeting mGluRS show only modest efficacy in humans (Berry-Kravis et al., 2012). Three factors have contributed to the human findings, (a) Multiple pathways are affected in FXS; thus, targeting only a single pathway is unlikely to fully correct the complex phenotype. Additional targets must be identified so that a polypharmaceutical approach can be developed, (b) The outcome measures used in many clinical trials are not adequate for detecting subtle but meaningful treatment effects. (3) Important treatment-induced changes in brain function may produce only modest short-term changes in observable behavior in individuals with FXS, who have a history of missed and non-normative learning opportunities prior to treatment. It may be possible, however, to "boost" the phenotypic effects of a drug by adding a behavioral intervention to take advantage of improved brain function.