Neurodevelopment and early pharmacological interventions in Fragile X Syndrome

Abstract

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the leading monogenic cause of autism and intellectual disability. For years, several efforts have been made to develop an effective therapeutic approach to phenotypically rescue patients from the disorder, with some even advancing to late phases of clinical trials. Unfortunately, none of these attempts have completely succeeded, bringing urgency to further expand and refocus research on FXS therapeutics. FXS arises at early stages of postnatal development due to the mutation and transcriptional silencing of the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1) and consequent loss of the Fragile X Messenger Ribonucleoprotein (FMRP) expression. Importantly, FMRP expression is critical for the normal adult nervous system function, particularly during specific windows of embryogenic and early postnatal development. Cellular proliferation, migration, morphology, axonal guidance, synapse formation, and in general, neuronal network establishment and maturation are abnormally regulated in FXS, underlying the cognitive and behavioral phenotypes of the disorder. In this review, we highlight the relevance of therapeutically intervening during critical time points of development, such as early postnatal periods in infants and young children and discuss past and current clinical trials in FXS and their potential to specifically target those periods. We also discuss potential benefits, limitations, and disadvantages of these pharmacological tools based on preclinical and clinical research.

Keywords: Fragile X syndrome; GABA; PI3K; clinical trials; mGluR; neurodevelopment; pharmacological interventions.

Figure 1

Human relative gene expression throughout development. FMR1, GABRD, GABRA5, GAD1, SLC12A2 and SLC12A5 genes from embryonic stages (post conceptional weeks, pcw) to adulthood of healthy human subjects. RNA-seq data were obtained from Brainspan Developmental Transcriptome, containing log2 RPKM (reads per kilobase per million) values. Orange dots shows expression from 4 months to 4 years. Genes analyzed were: (A) FMR1 (ENSG00000102081), (B) GABRD (ENSG00000187730), (C) GABRA5 (ENSG00000186297), (D) GAD1 (ENSG00000128683), (E) SLC12A2 (ENSG00000064651), (F) SLC12A5 (ENSG00000124140). RNA-seq data were obtained from Brainspan Developmental Transcriptome, publicly available at https://human.brain-map.org/.

Figure 2

Current FXS clinical trial status and age group addressed. (A) Completion and recruiting status for FXS clinical trials. (B) Percentage of FXS clinical trials per age group. (C) Starting age required for patients recruited in clinical trials by year from 2002 to 2022.