AUTHOR=Bui Truong An , Shatto Julie , Cuppens Tania , Droit Arnaud , Bolduc François V. TITLE=Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome JOURNAL=Frontiers in Psychiatry VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2021.730987 DOI=10.3389/fpsyt.2021.730987 ISSN=1664-0640 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.