Biomarker Discovery and Validation for Fragile X Syndrome

RESULTS PUBLISHED: Altered steady state and activity-dependent de novo protein expression in fragile X syndrome

With a $120,000 grant from FRAXA Research Foundation over 2015-2016, Dr. Eric Klann and Dr. Heather Bowling of New York University, and Aditi Bhattacharya, PhD, of the National Centre for Biological Sciences, investigated potential biomarkers in Fragile X syndrome and how to translate these markers from mouse models to human patients.

klann lab

Heather Bowling, PhD
Postdoctoral Fellow

Eric Klann, PhD
Principal Investigator

Aditi Bhattacharya, PhD
Co-Principal Investigator
National Centre for Biological Sciences
Bangalore, India

New York University
2016 FRAXA Research Grant
$120,000 over 2 Years

Drug development efforts for Fragile X syndrome (FXS) have recently suffered significant setbacks with the under-performance of recent clinical trials. The FXS clinical and research community has scrutinized the outcome of these trials to better understand the reasons for their disappointing results and to propose better strategies for future therapeutic development efforts. From these discussions, there is a consensus that there is a lack of unbiased outcome measures to adequately evaluate the performance of new therapeutics in clinical trials. Hence, there is a critical need to develop reliable and relevant biomarkers to examine the efficacy of new therapeutics currently in development.

Because protein synthesis changes have been previously implicated in Fragile X syndrome pathology in animal models and humans, we asked if differences in protein expression could provide key candidates for biomarkers in human patients. To examine changes in proteins in the brains of FXS model mice, we developed a combinatorial proteomic technique to detect and quantify changes in the landscape of basal and activity-protein synthesis. We applied this technique to analyze the protein expression profile of FXS model mouse hippocampi versus wild-type littermates, which has yielded candidates that can be potentially employed as biomarkers.

With funding from this program grant from the FRAXA Research Foundation, we aim to develop a biomarker system that is a) easy to perform across multiple sites, b) can be applied to a heterogeneous patient population, and c) would be capable of providing unbiased metrics for monitoring patient performance and response to therapies, independent of behavioral and psychological tests. In addition, we will determine which potential biomarkers identified in FXS animal models translate to the clinic, both from new candidates from our proprietary screen and those previously identified in FXS literature. Results from these studies will provide valuable information to characterize the limits of extrapolation at the molecular level from pre-clinical models to human disease states. We also hope to create a biomarker system that can be used for evaluation of efficacy and patient stratification to streamline interpretation of future clinical trial data.

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