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Abstract：
Fragile X syndrome (FXS) is the most common single-gene cause of intellectual disability and autism spectrum disorder. Individuals with FXS present with a wide range of severity in multiple phenotypes including cognitive delay, behavioral challenges, sleep issues, epilepsy, and anxiety. These symptoms are also shared by many individuals with other neurodevelopmental disorders (NDDs). Since the discovery of the FXS gene, FMR1, FXS has been the focus of intense preclinical investigation and is placed at the forefront of clinical trials in the field of NDDs. So far, most studies have aimed to translate the rescue of specific phenotypes in animal models, for example, learning, or improving general cognitive or behavioral functioning in individuals with FXS. Trial design, selection of outcome measures, and interpretation of results of recent trials have shown limitations in this type of approach. We propose a new paradigm in which all phenotypes involved in individuals with FXS would be considered and, more importantly, the possible interactions between these phenotypes. This approach would be implemented both at the baseline, meaning when entering a trial or when studying a patient population, and also after the intervention when the study subjects have been exposed to the investigational product. This approach would allow us to further understand potential trade-offs underlying the varying effects of the treatment on different individuals in clinical trials, and to connect the results to individual genetic differences. To better understand the interplay between different phenotypes, we emphasize the need for preclinical studies to investigate various interrelated biological and behavioral outcomes when assessing a specific treatment. In this paper, we present how such a conceptual shift in preclinical design could shed new light on clinical trial results. Future clinical studies should take into account the rich neurodiversity of individuals with FXS specifically and NDDs in general, and incorporate the idea of trade-offs in their designs.
摘要：
脆性X综合征（FXS）是智力障碍和自闭症谱系障碍最常见的单基因原因。具有FXS的个体在多种表型中表现出广泛的严重程度，包括认知延迟，行为挑战，睡眠问题,癫痫,和焦虑。这些症状也被许多患有其他神经发育障碍(NDD)的个体所共有。自从FXS基因被发现以来,FMR1，FXS一直是激烈的临床前研究的重点，并被置于NDD领域临床试验的最前沿。到目前为止,大多数研究都旨在翻译动物模型中特定表型的拯救，例如,学习,或改善FXS患者的一般认知或行为功能。试验设计,结果衡量标准的选择，和对最近试验结果的解释显示了这种方法的局限性.我们提出了一种新的范式，其中将考虑与FXS个体有关的所有表型，更重要的是,这些表型之间可能的相互作用。这种方法将在基线，这意味着当进入试验或研究患者群体时，以及在干预后，当研究对象已经暴露于研究产品时。这种方法将使我们能够进一步了解潜在的权衡，这些权衡是临床试验中治疗对不同个体的不同影响的基础。并将结果与个体遗传差异联系起来。为了更好地理解不同表型之间的相互作用，我们强调,在评估特定治疗时,需要进行临床前研究,以调查各种相互关联的生物学和行为结局.在本文中,我们介绍了临床前设计的这种概念转变如何为临床试验结果提供新的思路.未来的临床研究应该考虑到FXS患者和NDD患者的丰富神经多样性，并将权衡的想法融入他们的设计中。
