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. 2024 Mar 1;134(5):e175036.
doi: 10.1172/JCI175036.

Challenges in developing therapies in fragile X syndrome: how the FXLEARN trial can guide research

Jeffrey L Neul

Challenges in developing therapies in fragile X syndrome: how the FXLEARN trial can guide research

Jeffrey L Neul. J Clin Invest. .

Abstract

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and the single-gene cause of autism, is caused by decreased expression of the fragile X messenger ribonucleoprotein protein (FMRP), a ribosomal-associated RNA-binding protein involved in translational repression. Extensive preclinical work in several FXS animal models supported the therapeutic potential of decreasing metabotropic glutamate receptor (mGluR) signaling to correct translation of proteins related to synaptic plasticity; however, multiple clinical trials failed to show conclusive evidence of efficacy. In this issue of the JCI, Berry-Kravis and colleagues conducted the FXLEARN clinical trial to address experimental design concerns from previous trials. Unfortunately, despite treatment of young children with combined pharmacological and learning interventions for a prolonged period, no efficacy of blocking mGluR activity was observed. Future systematic evaluation of potential therapeutic approaches should evaluate consistency between human and animal pathophysiological mechanisms, utilize innovative clinical trial design from FXLEARN, and incorporate translatable biomarkers.

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Conflict of interest statement

Conflict of interest: JLN receives research support from Acadia Pharmaceuticals.

Figures

Figure 1
Figure 1. Development of clinical therapies in FXS requires mechanistic targets, translatable preclinical models, and rigorous trial design.
Expansion of CGG trinucleotide repeats (more than 200) within the promoter of the FMR1 gene results in promoter hypermethylation, transcriptional silencing, and decreased FMRP expression and causes FXS. FMRP is a ribosomal-associated RNA-binding protein that is involved in translational repression, is localized to neuronal dendrites, and regulates activity-dependent protein synthesis related to synaptic plasticity. Animal models suggest decreasing mGluR signaling might correct protein translation related to synaptic plasticity and improve phenotypes; however, multiple clinical trials have failed to show efficacy of this approach. The FXLEARN clinical trial (12) included an innovative study design, incorporating young children, combining pharmacological and learning interventions, and prolonging the treatment period. However, no efficacy of blocking mGluR activity was observed. Future studies should align human and animal pathophysiological mechanisms with rigorous clinical study design.
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Comment on

  • Effects of AFQ056 on language learning in fragile X syndrome

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