2014 Gordon Conference/Seminar on Fragile X & Autism-Related Disorders: Advances in human therapy

描述（申请人提供）：脆性X综合征（FXS）是遗传性智力缺陷的最常见形式，也是自闭症最常见的单基因原因， 5,000名男性和少数女性。自闭症谱系障碍（ASD）发生在多达2/3的男性和1/3的女性FXS。脆性X基因（FMR 1）于1991年被克隆，从那时起，一个大的领域已经发展到一百多个实验室，使用从生物化学到遗传学的技术来模拟生物体，以阐明FMR 1蛋白（FMRP）的功能。FMRP主要是一种多核糖体相关蛋白，其调节高度富集突触蛋白的一组信息的翻译。除了调节翻译外，已经发现FMRP与特定的mRNA子集相互作用并伴随其到达突触。在这些突触中，FMRP是一个关键的开关，它介导局部蛋白质表达的变化以响应神经活动，导致突触响应经验而增强或减弱。已经提出了特定的信号传导机制来介导这种控制，包括I组代谢型谷氨酸受体。此外，已经发现了大量关于FMRP功能丧失对树突棘动力学的影响，以及不同脑区中突触传递的改变，并且理解已经扩展到突触反应改变对模型生物中电路功能和学习的影响。很明显，除了FXS和自闭症谱系障碍（ASD）之间的临床重叠之外，这两种疾病的分子病理学可能存在大量重叠。因此，已知引起ASD和其他神经发育障碍（NDD）的分子缺陷可能涉及受FMRP活性调节或调节FMRP活性的信号传导途径中的其他蛋白质，可能涉及其翻译受FMRP调节的蛋白质，或可能涉及在FXS模型中显示失调的神经递质系统中的缺陷。针对这些途径的分子目前正在学术实验室和制药行业进行开发和测试，以便为FXS患者提供有效的药物治疗。预计这些靶向治疗中的许多将在患有ASD或NDD的个体的子集中具有治疗重叠。本次会议将汇集脆性X，ASD和NDD领域的领先科学家和临床医生，特别是那些研究ASD/NDD形式的人，这些ASD/NDD的分子途径与FXS中涉及的分子途径重叠。主题将包括ASD和相关疾病遗传学的最新发展，FMRP功能及其调节，分子和遗传水平疾病之间的重叠，模型系统表征，树突棘动力学和突触可塑性研究，结果测量，以及在FXS和ASD/NDD人类中的治疗试验。该会议预计将加快临床转化研究的步伐，为FXS和ASD相关疾病患者带来重要的靶向治疗。

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited intellectual deficiency and the most frequent single gene cause of autism, affecting 1 in 5,000 males and a lesser number of females. Autism spectrum disorders (ASD) occur in up to 2/3 of males and 1/3 of females with FXS. The Fragile X gene (FMR1) was cloned in 1991 and since then a large field has grown with more than a hundred labs using techniques from biochemistry through genetics to model organisms to elucidate the functions of the FMR1 protein (FMRP). FMRP is primarily a polyribosome-associated protein that regulates the translation of a set of messages highly enriched for synaptic proteins. In addition to regulating translation FMRP has been found to interact with and accompany a specific subset of mRNAs to synapses. At those synapses, FMRP is a critical switch that mediates changes in local protein expression in response to neural activity, causing synapses to strengthen or weaken in response to experience. Specific signaling mechanisms have been proposed to mediate this control, including group I metabotropic glutamate receptors. In addition, a great deal has been discovered about the effects of loss of FMRP function on dendritic spine dynamics, and altered synaptic transmission in various brain areas, and understanding has been extended to the impact of altered synaptic responses on circuit function and learning in model organisms. It has become clear that in addition to the clinical overlap between FXS and autism spectrum disorders (ASD), there is likely substantial overlap in the molecular pathology of the two disorders. As such, molecular defects known to cause ASD and other neurodevelopmental disorders (NDD) may involve other proteins in the signaling pathways that are regulated by or regulate FMRP activity, may involve proteins whose translation is regulated by FMRP, or may involve defects in neurotransmitter systems shown to be dysregulated in FXS models. Molecules aimed at targets in such pathways are now being developed and tested in academic laboratories and through the pharmaceutical industry, in order to offer effective drug therapies for patients with FXS. It is expected that many of these targeted treatments will have therapeutic overlap in subsets of individuals with ASD or NDD. This conference will bring together leading scientists and clinicians in the Fragile X, ASD, and NDD fields, particularly those working on forms of ASD/NDD with dysfunctions in molecular pathways that overlap those implicated in FXS. Topics will include the latest developments in genetics of ASDs and related diseases, FMRP function and its regulation, the overlap between the diseases at the molecular and genetic level, model system characterizations, dendritic spine dynamics and synaptic plasticity studies, outcome measures, and translation to treatment trials in humans with FXS and ASD/NDD. The conference is expected to accelerate the pace of bench-to-bedside translational research to bring important targeted treatments to individuals with FXS and ASD-related disorders.