Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome.

Truong An Bui,François V Bolduc,Julie Shatto,Arnaud Droit,Tania Cuppens

doi:10.3389/fpsyt.2021.730987

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.

Highlights

Neurodevelopmental Disorders AreCharacterized by Diverse and ComplexPhenotypic TraitsThe term neurodevelopmental disorders (NDDs) refers to a group of disorders marked by impairments of human functioning, including personal, social, academic, and occupational functions [1]
As Kelley et al demonstrated, the levels of cyclic adenosine monophosphate (cAMP) were low in the amygdala in FMR1 KO mice [127], which suggests that PDE inhibitors might compensate for this defect in FXS patients
It is clear that more studies need to be done to test the hypothesis that we propose, which outlines that pharmacological interventions must account for potential interacting phenotypic trade-offs

Summary

INTRODUCTION

The term neurodevelopmental disorders (NDDs) refers to a group of disorders marked by impairments of human functioning, including personal, social, academic, and occupational functions [1]. While the trials failed to deliver desirable outcomes, their results could be explained with an analysis of phenotypic trade-offs, by considering the interrelationships between cognitive skills (TP) and anxiety (UP) This is possible as increased anxiety has been shown in the literature to negatively affect cognitive performance in general [96, 97] and in FXS in particular [98]. The study showed a trend of improvement in anxiety, as the treatment group scored a mean of −1.41 on the ADAMS scale compared to the placebo group (−0.79), the statistical result was not significant (Table 1) From these studies, we attempt to explain how phosphodiesterase (PDE) inhibitors could possibly lead to cognitive improvement without elevating anxiety as was seen in the case of mGluR inhibitors (Table 1). As Kelley et al demonstrated, the levels of cAMP were low in the amygdala in FMR1 KO mice [127], which suggests that PDE inhibitors might compensate for this defect in FXS patients

DISCUSSION

A NEW APPROACH

Findings

DATA AVAILABILITY STATEMENT