New Biomarker Discovery for Fragile X Syndrome: From Mouse Brains to Patient Blood

Background: Recent clinical trials for treating the leading single gene cause of autism, fragile X syndrome (FXS), have failed in part due to a lack of biomarkers that can readily detect treatment–driven improvements and/or that can stratify the diverse FXS population. Using a novel brain-based proteomic approach, we identified proteins whose synthesis is dysregulated in FXS mice. Gene ontology analysis revealed that proteins related to metabolism, synaptic function, and intracellular signaling cascades are inappropriately synthesized in FXS mouse model brains.

Objectives: Many of the brain proteins we identified can be detected in more accessible tissues, such as blood. Therefore, we asked whether the blood levels of these proteins correlated with treatment response in FXS mice and whether any protein levels differed between FXS patients and healthy controls in plasma.

Methods: We measured the response of two proteins identified in our screen in the blood of FXS mice following three treatments shown previously to be effective in reversing phenotypes in FXS mice: PF-4708671, lithium and metformin. We then measured an expanded panel of seven proteins in human plasma, comparing 11 healthy volunteers to 11 FXS patients.

Results: In each treatment group for the FXS mice, we measured a difference in at least one marker in the drug-treated group compared to the vehicle group. Three of the seven proteins measured in human plasma showed a clear difference between healthy volunteers and FXS patients, with two additional proteins suggesting subpopulations within the FXS patient group.

Conclusions: Our data suggest that the markers identified in FXS model mouse brains are measureable in blood and may predict efficacy for drug treatment and could provide information for patient stratification for future clinical trials.