Finding Fragile X Biomarkers – From Transcriptomics to Behavior in Patients

by Peter Vanderklish, PhD

A biomarker is a molecule (a specific protein, mRNA, or metabolite) or biological process (like an EEG rhythm) that can be precisely measured and reveals something about an underlying disease process and the effects of candidate treatments. Biomarkers are of tremendous value in clinical trials: they provide investigators with independent, objective measures of disease severity and how well a candidate therapeutic has “engaged the target” and/or normalized disease processes. They helps clinicians look for meaningful patterns among those who respond to a candidate treatment vs those who don’t in a trial.

At present, there is an urgent need to establish reliable biomarkers of FXS so that drug therapies emerging from preclinical research can be tested quickly and efficiently. Ideally, molecular biomarkers would be available that can be assessed non-invasively, as in blood cells.

In this project, we are searching in platelets for mRNAs and proteins that show significant changes in expression level in FXS patients, relative to age and sex-matched controls. Platelets are small non-nucleated cells involved in blood clotting. In many ways, they resemble synapses and even contain significant numbers of synaptic mRNAs and proteins that are thought to be involved in FXS. What’s more, they are easily accessible.

Dr. Julie PIlotte in the Vanderklish lab will search for changes in platelet messenger RNAs utilizing a method called “RNAseq”, whereby all mRNA transcripts in platelets (i.e. the “transcriptome”) can be quantified and compared between FXS subjects and controls.

For protein measurements, we will take a more targeted approach that is guided by proteins of interest in our laboratory and the broader FXS field, and by the results of our RNAseq studies. The hope is that we will obtain reliable new molecular biomarkers in platelets that can offer an easy way to stratify FXS patients by (i) the severity of underlying disease processes and (ii) the likelihood that they will respond to new treatment approaches. In addition, there is the possibility that we will identify new molecular abnormalities that may serve as a basis for the development of new drug therapies.

This project adds to a very unique and exciting project initiated by Dr. Patricia Cogram at FRAXA-DVI. Dr. Cogram is the director of the FRAXA-funded Biomarker Project, in collaboration with Dr. Paulina Carulo, MD, a Child Neurologist and clinical project coordinator at the FLENI Institute, Argentina. In the Biomarker Project, a population of drug-naïve FXS patients and age/sex-matched controls are being studied at multiple levels to provide a highly detailed characterization of this FXS study population. This includes in-depth cognitive assessments and new EEG approaches to find novel behavioral and neural activity metrics that can be used to evaluate the efficacy of new treatments.

We will perform our molecular studies on platelets collected from these patients by Dr Mauricio Farez, MD, PhD, who leads FLENI’s clinical lab. The molecular data we generate from patient platelets will complement data derived from higher order outcome measures (e.g. EEG and behavior) in assessing target engagement and efficacy of new drug treatments. Dr Marta Cordoba, MD, PhD, a neurologist and geneticist on Dr. Cogram’s team, will perform the analysis of platelet transcriptomic data.

This is the first time that all these different levels of study – from transcriptomics to behavior – have been done for individual patients with Fragile X.

We wish to acknowledge and thank the families of the Fragile X Parents Association of Argentina for participating in these important studies.