Effects of AFQ056 on Language Learning in Young Children with Fragile X Syndrome (FXS)

AFQ056 对患有脆性 X 综合征 (FXS) 的幼儿语言学习的影响

• 批准号: 9120161
• 负责人: LEONARD J. ABBEDUTO
• 金额: $ 347.35万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120161
• 关键词: Accounting; Adolescent; Adult; Age; Animal Model; Animals; Autistic Disorder; Behavior; Behavioral; Binding Proteins; Biological Assay; Biological Markers; Brain; Cellular Morphology; Child; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Dendritic Spines; Development; Developmental Course; Disease; Disease model; Dose; Double-Blind Method; Drosophila genus; Drug Targeting; Electrophysiology (science); Equilibrium; Event-Related Potentials; Exposure to; Eye; FMR1; Fragile X Syndrome; Future; Genes; Genetic; Goals; Growth; Human; Individual; Inherited; Intellectual functioning disability; Intervention; Language; Language Development; Lead; Learning; Literature; Maximum Tolerated Dose; Measurement; Measures; Messenger RNA; Modeling; Molecular; Mus; Nature; Neurobiology; Neurodevelopmental Disability; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurosciences; Neurosciences Research; Outcome; Parents; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Placebo Control; Placebos; Population; Pre-Clinical Model; Process; Proteins; Publications; Randomized; Receptor Activation; Research; Safety; Signal Pathway; Signal Transduction; Synapses; Synaptic plasticity; System; Testing; Time; Titrations; Translations; Work; autism spectrum disorder; behavioral outcome; conditioning; design; developmental disease; drug development; fenobam; flexibility; follow-up; improved; innovation; meetings; open label; overexpression; pre-clinical; preclinical study; public health relevance; skills; small molecule; social; synaptic function; theories; trial design

 DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. Enormous progress in basic and translational FXS research has allowed identification of neuronal pathway targets for treatment of the underlying disorder. The most well-studied of these has been pharmacological (using mGluR5 negative allosteric modulators (NAMs)) and genetic reduction of excessive mGluR5 translational pathway signaling to correct abnormal synaptic plasticity, dendritic morphology, cellular signaling, electrophysiological, cognitive, social, behavioral and even growth phenotypes in FXS models. Human early phase trials of mGluR5 NAMs fenobam (Neuropharm), AFQ056 (Novartis) and RO4917523 (Roche) have suggested possible benefit in FXS, but larger phase IIb studies of AFQ056 and RO4917523 failed to meet primary behavioral outcomes in adolescents/adults. These trials may have failed due to lack of measurement of core FXS phenotypes of cognition and learning in a sufficiently young population over a long enough period of time. The proposed project will seek to determine whether the human mGluR5 NAM trials failed because the animal model is not adequate or because the trials were not conducted in a way that benefit could be seen in a neurodevelopmental disorder (NDD). Indeed it may be that the benefits of translational work from preclinical models of NDDs can never be realized via standard drug development pathways. This NeuroNEXT trial seeks to use an innovative exploratory design to change the paradigm for translation of targeted treatments in FXS and determine whether AFQ056 can improve language learning in 100 very young (age 3-6 years) children with FXS during participation in an intensive language learning intervention (LLI), as a surrogate for enhanced neural plasticity. The trial will use a double blind placebo-controlled parallel flexible- dose forced-titration design with a 4 month placebo-lead-in, randomization to AFQ056 or placebo and titration to maximum tolerated dose (MTD), 6 months treatment with AFQ056/placebo combined with the LLI, an open- label extension with re-titration to MTD followed by 6 months of treatment of all participants with LLI and AFQ056, and follow up off AFQ056 at the end of the trial. The study will seek to assess effects of AFQ056 versus placebo on developmental (language, cognitive, adaptive and maladaptive) functioning in young children with FXS receiving the LLI (Aim 1), evaluate safety and tolerability of long-term exposure to AFQ056 in young children with FXS (Aim 2), validate biomarkers that interrogate neural functioning (event-related potentials and eye tracking) and cellular pathway signaling during treatment with AFQ056 and/or LLI and correlate these with developmental outcomes (Aim 3), validate the LLI by evaluating its effects on trajectories of language, cognitive, adaptiv, and maladaptive functioning (Aim 4). If the design is successful, this trial can serve as a model for future trials of mechanistically-targeted treatments operating on neural plasticity in other NDDs, and can accelerate the process of bringing needed treatments to these disorders with high unmet need.

 描述（应用程序提供）：脆弱的X综合征（FXS）是智力残疾和自闭症谱系障碍的最常见的遗传原因。基本和转化FXS研究中的巨大进展允许鉴定神经元途径靶标，以治疗潜在疾病。其中最充分研究的是药理（使用MGLUR5阴性变构调节剂（NAMS））和过量MGLUR5转化途径信号传导的遗传减少，以纠正异常突触可塑性，树突状形态，细胞信号传导，电流学，社会生理，社会，社会，行为，偶数均匀的模型。 MGLUR5 NAMS Fenobam（Neuropharma），AFQ056（Novartis）和RO4917523（Roche）的人类早期试验提出了FXS可能的好处，但是对AFQ056和RO4917523的IIB阶段研究较大，未能满足成人/成年成年人/成年成年人/成人的一级行为。由于缺乏足够长的年轻人群中核心FXS表型的测量，这些试验可能失败了。拟议的项目将寻求确定人类MGLUR5 NAM试验是否失败，因为动物模型不足，或者是因为未在神经发育障碍（NDD）中看到益处的方式进行试验。的确，可能永远无法通过标准药物开发途径实现转化工作的转化工作的好处。这项Neuronext试验试图使用创新的探索性设计来改变FXS中有针对性治疗的范例，并确定AFQ056是否可以改善100名非常年轻（3-6岁）的FX儿童在参与激烈的语言学习干预（LLI）（LLI）期间有FXS的儿童，以增强神经性塑性性。该试验将使用双重安慰剂对照平行的柔韧性强制性屈服设计，其安慰剂导量为4个月，随机化到AFQ056或安慰剂或安慰剂，以及滴定剂量最大耐受剂量（MTD），6个月以AFQ056的治疗与LLI进行了6个月的治疗，并与LLI进行了6个月的分组，并与lli的分期率一起进行，将其与RE-LABELITION一起进行，以MTITRI的延伸为单位，并将其用于MTTITRI，MTLI均与MTTIRI一起进行。和AFQ056，并在审判结束时跟进AFQ056。 The study will seek to assess effects of AFQ056 versus placebo on developmental (language, cognitive, adaptive and maladaptive) functioning in young children with FXS receiving the LLI (Aim 1), evaluate safety and tolerability of long-term exposure to AFQ056 in young children with FXS (Aim 2), validate biomarkers that interrogate neural functioning (event-related potentials and eye tracking) and cellular pathway使用AFQ056和/或LLI处理期间的信号传导，并将其与发育结果相关联（AIM 3），通过评估其对语言轨迹，认知，适应性和不良适应功能的影响来验证LLI（AIM 4）。如果设计成功，则该试验可以作为对其他NDD中神经可塑性的机械靶向治疗方法的未来试验的模型，并可以加速为这些疾病带来高度未满足的疾病的过程。