Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Aug 2:17:1213410.
doi: 10.3389/fnins.2023.1213410. eCollection 2023.

Neurodevelopment and early pharmacological interventions in Fragile X Syndrome

Luis A Milla  1 , Lucia Corral  2 , Jhanpool Rivera  2 , Nolberto Zuñiga  2 , Gabriela Pino  2 , Alexia Nunez-Parra  3   4 , Christian A Cea-Del Rio  2
Affiliations
Review

Neurodevelopment and early pharmacological interventions in Fragile X Syndrome

Luis A Milla et al. Front Neurosci. .

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.

PubMed Disclaimer

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
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
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.
See this image and copyright information in PMC

References

    1. Alpatov R., Lesch B. J., Nakamoto-Kinoshita M., Blanco A., Chen S., Stützer A., et al. . (2014). A chromatin-dependent role of the Fragile X mental retardation protein FMRP in the DNA damage response. Cells 157, 869–881. doi: 10.1016/j.cell.2014.03.040 - DOI - PMC - PubMed
    1. Altable M., de la Serna J. M. (2021). Neuroinflammation links COVID-19 and fragile X syndrome: role of MMP-9, IGF-1, IL-10, metformin, statins and curcumin. Qeios. doi: 10.32388/KO4C77.2 - DOI
    1. Antoine M. W., Langberg T., Schnepel P., Feldman D. E. (2019). Increased excitation-inhibition ratio stabilizes synapse and circuit excitability in four autism mouse models. Neuron 101, 648–661.e4. doi: 10.1016/j.neuron.2018.12.026 - DOI - PMC - PubMed
    1. Bailey D. B., Berry-Kravis E., Wheeler A., Raspa M., Merrien F., Ricart J., et al. . (2015). Mavoglurant in adolescents with fragile X syndrome: analysis of clinical global impression-improvement source data from a double-blind therapeutic study followed by an open-label, long-term extension study. J. Neurodev. Disord. 8, 1–10. doi: 10.1186/s11689-015-9134-5 - DOI - PMC - PubMed
    1. Bausch A. E., Dieter R., Nann Y., Hausmann M., Meyerdierks N., Kaczmarek L. K., et al. . (2015). The sodium-activated potassium channel slack is required for optimal cognitive flexibility in mice. Learn. Mem. 22, 323–335. doi: 10.1101/lm.037820.114 - DOI - PMC - PubMed