Targeted treatments for fragile X syndrome

Elizabeth Berry-Kravis, Andrew Knox, Crystal Hervey, Elizabeth Berry-Kravis, Andrew Knox, Crystal Hervey

Abstract

Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders.

Figures

Fig. 1
Fig. 1
Synaptic translation and signaling pathways modulated by FMRP (a) and dysregulation of these pathways in the absence or significant reduction of FMRP (b). Shaded areas in (b) indicate groups of targets for different strategies aimed at treatment of FXS by correcting dysregulated neuronal pathways. Shaded areas are numbered according to type of treatment strategy and correspond to numbering system for treatment strategies in the text as follows: (1) reduction of activity in pathways that transduce signals from group 1 mGluRs or other Gq-linked receptors to the dendritic translational machinery via (1a) extracellular pathway (receptor) blockers and/or (1b) intracellular pathway blockers; (2) reduction of activity of individual proteins regulated by FMRP; (3) increasing surface AMPA receptors and/or activity; (4) modification of activity of other receptors/proteins that regulate synaptic activity; and (5) blocking translation of mRNAs regulated by FMRP using antisense technology
Fig. 2
Fig. 2
Classes of potential overlap in synaptic mechanisms between ASD genes/proteins and pathways involved in FXS: (1) proteins involved in other forms of ASD may be in the signaling cascade for activation of FMRP-regulated translation; (2) FMRP may directly regulate proteins involved in different forms of ASD; and (3) convergence of glutamate and GABA pathway defects in FXS and ASD due to dysregulation of proteins generally important in maintaining inhibitory/excitatory balance and balance of activity in brain glutamate and GABA systems

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