Progress and Hurdles in Development of Targeted Treatments for Fragile X Syndrome

Background: Fragile X syndrome (FXS) is the most common known genetic cause of intellectual disability and autistic spectrum disorder. Recent major advances have been made in the understanding of the neurobiology and functions of the Fragile X Mental Retardation 1 (FMR1) gene product, the fragile X mental retardation protein (FMRP), which is absent or reduced in FXS. These advances, based largely on work in the Fmr1 knockout mouse model, have revealed FXS to be a disorder of synaptic plasticity associated with abnormalities of long-term depression, long-term potentiation and immature dendritic spine architecture, related to dysregulation of dendritic translation typically activated by group I mGluR and other Gq-linked receptors. 

Objectives: To test whether neuroactive molecules that target pathways dysregulated in the absence of FMRP in FXS animal models, can be translated to treat humans with FXS.

Methods: Multiple pilot open label, phase 2 and a few phase 3 clinical trials of various designs have been performed with FXS subjects to evaluate safety and efficacy of compounds that rescue molecular, spine, and behavioral phenotypes in the animal models and target underlying biological mechanisms in FXS.

Results: Pilot open label trials of lithium (reduces translation pathway signaling), minocycline (reduces MMP-9 activity) and acamprosate (GABA-A and –B agonist), lovastatin (indirect reduction of ERK and translation pathway signaling), and fenobam (mGluR5 blocker, Neuropharm LTD) suggested drug benefits in FXS and identified possible biomarkers. Small phase 2 proof of concept trials with arbaclofen (GABA-B agonist, Seaside Therapeutics), AFQ056 (mGluR5 blocker, Novartis), and minocycline suggested efficacy in FXS in some primary and post-hoc analyses. Phase 3 trials with arbaclofen, AFQ056, and RO4917526 (mGluR5 blocker, Roche) failed to meet primary behavioral endpoints in older populations. Arbaclofen demonstrated benefits in the 5-11 year old group however financial issues have stalled further development. Results not currently published from some of these trials will be presented as well as an autopsy conducted by Fragile X Clinical and Research Consortium investigators of the arbaclofen trials to better define areas of subject responses.

Conclusions: Attempts to translate findings in animal models of FXS to humans have raised complex issues about trial design and outcome measures to assess disease-modifying changes that might be associated with treatment. It will be important to adjust future trial designs and drug development plans to better test effects on synaptic plasticity by studying younger subjects for longer periods of time; studying cognition, developmental, language and functional measures in addition to behavior; implementing more objective clinician administered and direct observational outcome measures instead of parent rating forms; identifying biomarkers to detect response and identify potential responders; and by comparing drug vs placebo effects on response to intensive training interventions embedded in trials. Genes known to be causes of autistic spectrum disorders interact with the translational pathway defective in FXS, and it is likely that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction. Thus targeted treatment and clinical trial strategies in FXS may serve as a model for ASD and other cognitive disorders.