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Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome
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 sympto...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558248/ https://www.ncbi.nlm.nih.gov/pubmed/34733188 http://dx.doi.org/10.3389/fpsyt.2021.730987 |
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author | Bui, Truong An Shatto, Julie Cuppens, Tania Droit, Arnaud Bolduc, François V. |
author_facet | Bui, Truong An Shatto, Julie Cuppens, Tania Droit, Arnaud Bolduc, François V. |
author_sort | Bui, Truong An |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8558248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85582482021-11-02 Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome Bui, Truong An Shatto, Julie Cuppens, Tania Droit, Arnaud Bolduc, François V. Front Psychiatry Psychiatry 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. Frontiers Media S.A. 2021-10-18 /pmc/articles/PMC8558248/ /pubmed/34733188 http://dx.doi.org/10.3389/fpsyt.2021.730987 Text en Copyright © 2021 Bui, Shatto, Cuppens, Droit and Bolduc. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Psychiatry Bui, Truong An Shatto, Julie Cuppens, Tania Droit, Arnaud Bolduc, François V. Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome |
title | Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome |
title_full | Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome |
title_fullStr | Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome |
title_full_unstemmed | Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome |
title_short | Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome |
title_sort | phenotypic trade-offs: deciphering the impact of neurodiversity on drug development in fragile x syndrome |
topic | Psychiatry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558248/ https://www.ncbi.nlm.nih.gov/pubmed/34733188 http://dx.doi.org/10.3389/fpsyt.2021.730987 |
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