Lovastatin corrects ERK pathway hyperactivation in fragile X syndrome: potential of platelet's signaling cascades as new outcome measures in clinical trials.

AIM: To establish whether platelets from fragile X syndrome (FXS) individuals recapitulate FXS mouse neurons' defects in ERK and Akt pathways, and to evaluate the effect of lovastatin on these pathways. METHODS: ERK and Akt phosphorylation (pERK, pAkt) statuses were assessed with quantitative Western blotting before and after a 12-week lovastatin trial. RESULTS: Levels of pERK and pAkt were increased in FXS platelets, and lovastatin specifically normalized ERK activity. Changes in ERK phosphorylation were correlated with clinical response to lovastatin. CONCLUSIONS: Platelets' signaling pathways provide biomarkers that can be used as treatment outcome measures in FXS clinical trials.

Effect of lovastatin on behavior in children and adults with fragile X syndrome: an open-label study.

Fragile X syndrome (FXS) results from dynamic mutations leading ultimately to the absence of expression of the Fragile X Mental Retardation Protein (FMRP). It is characterized by synaptic upregulated protein synthesis and immature dendritic spines associated with altered brain plasticity and cognitive functions. Recent work in Fmr1 knockout mice has shown that lovastatin, an inhibitor of Ras-ERK1/2, normalized hippocampus protein synthesis. We hypothesize that lovastatin, as a disease-modifying drug, would counterweigh the absence of FMRP and improve behavior. Here we report a phase I study to assess the safety and efficacy of lovastatin in individuals with FXS. A total of 15 patients (13 males, 6-31 years old) were treated with escalating doses of lovastatin (up to 40 mg) for three months. Their behavior were assessed before and after treatment using the Aberrant Behavioral Checklist--Community (ABC-C) total score (primary outcome), as well as domains of the FXS validated version of the ABC-C (secondary outcomes). The treatment was well tolerated and minimal side effects were reported. Significant improvement in the primary outcome (P<0.005), as well as in secondary outcomes, were observed in the majority of the subjects (12/15). We think that long-term sustained treatment with diseased-modifying drugs would be necessary in order to improve behavior and ultimately learning. Lovastatin, well known for its long-term security profile, would be a good candidate for that purposes. Our study showing reassuring safety data along with potential functional benefit emphasizes the need of a placebo-controlled trial to ascertain lovastatin efficacy in FXS individuals.