Review Looks at Current Research into Friedreich’s Ataxia Biomarkers

Biomarkers for Friedreich’s ataxia (FA) may come from measurements of frataxin (FXN) levels in red blood cells and energy production in calf cells, imaging approaches in the nervous system and the heart, as well as markers of nerve cell damage, according to a review of ongoing work.

The research, “The current state of biomarker research for Friedreich’s ataxia: a report from the 2018 FARA biomarker meeting,” was published in the journal Future Science OA.

Clinical trials conducted to date in FA have been using clinical scales to measure disease progression. However, they have been conducted over a period of less than a year, which has been found to be insufficient to detect significant benefits of potential therapies on disease progression.

Having FA biomarkers may help find treatment candidates likely to be effective, which could then be tested in longer and more expensive studies. The 2018 Friedreich’s Ataxia Biomarker Meeting intended to review where biomarker development in FA stands and determine the next steps in those biomarkers’ development.

One current therapeutic strategy is to increase FXN protein levels, which are lower in these patients. A novel assay to measure active and mature isoforms (variants) of FXN may present a way to assess the effect of such treatments. The method, presented by University of Pennsylvania professor Ian Blair, intends to overcome limitations in quantifying blood FXN levels by focusing on a FXN variant called isoform E, produced in erythrocytes (red blood cells).

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In unaffected controls, this isoform is found at three times the levels in erythrocytes than the normal FXN protein in other blood cells. Importantly, the team found that patients with FA have a reduction in isoform E of over 70%, which the researchers said might be “a useful biomarker in studies of FXN upregulating therapies.” Although it still requires validation, the assay may be amenable for protein measurements in muscle biopsies.

Histone deacetylase inhibitors (HDACi) have been developed to raise FXN levels, but studies have suggested that their success may depend on a balance between epigenetic changes, which refer to alterations in gene expression, rather than in the FXN gene itself. A team at the University of Oklahoma Health Sciences Center found that the degree of methylation — a type of epigenetic change, consisting of the addition of methyl chemical groups — at a key site may predict the ability to reactivate FXN gene expression.

Presented by Sanjay Bidichandani, PhD, early data in 48 FA patients revealed that lower methylation correlates with greater response to HDACi treatment in FA, and thereby may be an effective biomarker to predict who will respond to such therapies.

In turn, investigators at the University of Alabama at Birmingham have been using large-scale protein screening to study potential changes in cells called fibroblasts and in the serum of FA patients. One of the proteins found at increased levels in these patients was the ALDH1A3 enzyme, which correlated with the presence or absence of cardiomyopathy (heart muscle disease).

Also related to cardiac complications in this patient population, a group at France’s IGBMC Strasbourg found higher levels of the Gdf15 and Fgf21 genes in the heart tissue of mice, but studies to date did not find similar changes in humans.

Work at Children’s Hospital of Philadelphia has focused on metabolic changes in cells because of lower FXN levels. Experiments in adults and adolescents with FA used a technique called creatine chemical exchange saturation transfer (CrCEST) to measure energy production in calf muscle cells. Ultimately, the results suggested that this may become a longitudinal biomarker of muscle capacity in people with FA.

The same group also conducted the oral glucose tolerance test in this patient population. It revealed that people with FA but without diabetes mellitus have a higher fasting level of glucose, higher production of insulin and prolonged increase of lactate levels after the glucose load, as compared with controls.

Another approach currently used in FA biomarker research is neuroimaging. Besides biochemical changes, studies at the University of Minnesota found structural changes in patients’ cervical spinal cords. In both the spinal cord and in the brain, the experiments further showed lower nerve fiber density and diameter, as well as reduced myelin — the insulating layer of nerve fibers — in the white matter. Several of the imaging measurements correlated with the degree of disease severity.

Serum neurofilament light chain (sNfL) — a protein released by nerve cells upon damage — has been proposed as a biomarker of multiple sclerosis and spinal muscular atrophy. Two studies suggested that it could also be useful in FA, as patients had higher blood levels of sNfL than controls. Measures such as quantitative sensory testing, also presented at the meeting, showed the potential to detect changes in neurological function, but its applicability in a clinical trial remains to be demonstrated.

Cardiac biomarkers were the subject of six presentations, including both imaging technologies and serum biomarkers. One of these studies reviewed cardiac magnetic resonance imaging (cMRI), a technique feasible in most FA patients that provides data on cardiac function, structure, and volume. It has already been used in Brazil to show that FA patients have increased left ventricle mass, as well as larger fibers in the heart’s muscle, associated with worse neurological function.

Also using cMRI, scientists from the University of Florida developed a strategy called Cine-Balanced Steady State Free Precession that showed a link between early fibrosis (scarring) in the heart and cardiac outcome over time, even in patients currently without symptoms. Researchers at California-based BioMarin Pharmaceutical found that FA patients have increased levels of cardiac troponin, a well-established marker of cardiac damage during heart attacks.

Besides imaging and biochemical markers, experiments at Australia’s Melbourne School of Health Sciences revealed that dysphonia (difficulty speaking), as well as measures such as speech rate, duration, and pauses during paragraph reading correlated with neurological function in FA patients.

“Biomarker development for FA is progressing rapidly on several fronts,” the investigators said. “In the next 10 years, we anticipate many additional therapies reaching the clinic for FA, and the use of these biomarkers will enable faster trials that will give informative answers as to whether to continue development of the therapy. It is an exciting time for drug development in FA.”