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. 2021 Oct 18:12:730987.
doi: 10.3389/fpsyt.2021.730987. eCollection 2021.

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

Truong An Bui  1 , Julie Shatto  1 , Tania Cuppens  2 , Arnaud Droit  2 , François V Bolduc  1   3   4
Affiliations

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

Truong An Bui et al. Front Psychiatry. .

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.

Keywords: autism; clinical trials; fragile X syndrome; intellectual disability; neurodevelopmental disorder; neurodiversity; phenotype-genotype correlation; trade-off.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Phenotypic trade-offs can be conceptualized as variations between inter-related phenotypes. (A) Phenotypes are represented as separate entities. Viewing different phenotypes of a disorder as independent factors could impede the design and implementation phases of an intervention. (B) In its simplest form, 1:1 interactions of different phenotypes are seen. This can be visualized as the simpler seesaw model which suggests that two phenotypes, as illustrated in the red and blue boxes, have opposing relations, in which an increase in one phenotype (red) leads to a decrease in the other (blue). An example of that could be the balance between increased hyperarousal and decreased sleep. (C) As seen in FXS, different phenotypes interact and exacerbate the existing pathological effects on another phenotype. For instance, shown in this figure, is the additive effect of the red, yellow, and green boxes on the blue box. In addition, this second model depicts a tilting table atop three bases. These three bases reflect a more complicated model that takes into account the neuronal network, as well as multiple other underlying factors such as genetic makeups, epigenetics, and environmental factors, which could influence the presence of phenotypes (boxes), creating a more complex phenotypic output in the end.
Figure 2
Figure 2
Translational aspects related to phenotypic trade-offs. An important difference between preclinical studies in animal models and humans is the degree of inter-individual variability in phenotypes. (A) In animal models, especially the inbred models used in the laboratory, genetic background, and environmental conditions are controlled closely. This leads to very homogeneous phenotypes, as each circle represents a phenotype seen in FXS and the size of the circle is representing the severity of the phenotype. This allows behavioral researchers to obtain more significant results. As the weight of each phenotype is conserved between individual animals, so is the interaction between phenotypes. For instance, the cognition (TP) (red) is always facing the same weight of anxiety (UP) (blue). Thus, a drug aimed at the TP will always interact with the same amount of potential effect of UP. On the other hand, (B) in human phenotypes, both cognition and anxiety vary significantly between individuals, as the size of each circle represents the magnitude of the severity of the phenotype. Multiple reasons could explain this, including genetic background, variable genetic lesion in the target gene, environmental, epigenetic, demographic, etc. The variations in TP and UP can influence the impact of trade-offs. For instance, in participant #1, the impact of anxiety is much bigger than in participant #2. So a drug targeting cognition (TP) positively but also enhancing anxiety (UP) will seem to have a great effect in individual #2 but be detrimental to participant #1 or #3. In a more realistic scenario, there are more than two phenotypes interacting, hence, the relative balance of those phenotypes is often unknown in clinical trials, making it difficult to analyze and predict the outcomes of the intervention. FXS, fragile X syndrome; TP, target phenotype; UP, unexpected phenotype; OCD, obsessive-compulsive disorder.
Figure 3
Figure 3
Multiple biological factors contribute to the complexity of phenotypic trade-offs. Several general variables need to be considered in understanding the biological basis of phenotypic trade-offs, as seen with drug treatment. In the case of FXS, it is important to include the level of FXS protein, FMRP, as this has an effect on IQ. Mosaicism also influences the phenotypic severity of IQ and potentially other phenotypes. However, this is not well-understood. In addition, drug and gene-specific variables need to be taken into account, such as (1) brain region, (2) cell type, (3) synaptic location (pre vs. postsynaptic signaling), and (4) gene expression. For (1) brain region, we imply that the effects of gene mutation and drugs should be understood for all disorder-relevant circuits. For instance, patients with disorders could present a cognitive deficit as well as an excessive anxiety, such that both clinical and preclinical data for these two phenotypes should be assessed. The potential trade-offs between these two phenotypes should also be evaluated. (2) Cell type needs to be considered in terms of the patterns of gene expression and effects of the drug. For instance, FXS has a role in both excitatory and inhibitory neurons, and a drug affecting one and not the other may worsen the patient's condition where homeostasis should be conserved. Similarly, the imbalance between glia and neurons, and more recently, between microglia and inflammation could lead to unexpected effects. Changes in cells from specific cortical layers may affect network properties of one phenotype more than another. These could be more systematically investigated in the preclinical field to provide further insights. (3) Synaptic location plays an important role in the net effect of an intervention. As seen in the case of mGluR, it is important to understand the impact of regional variations in this distribution. Finally, variations in patterns of (4) gene expression within the brain, and in the body, probably play a major role in explaining changes in behavioral outputs. For instance, demographic factors, such as sex and age, have important impacts on the ability of a drug to affect a behavioral phenotype. What is more complex is that although developmental windows are altered in neurodevelopmental disorders, the window for each phenotype may not be delayed in the same way, leading to variable inter-phenotype relation overdevelopment, as well as the closure of some windows before others, which all affect observed trade-offs between phenotypes. FXS, fragile X syndrome; FMRP, fragile X mental retardation protein; IQ, intelligence quotient; PK, pharmacokinetics; PD, pharmacodynamics.
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