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UK Researchers Identify Pair of Potential Biomarkers for Multiple Sclerosis

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NEW YORK (360Dx) – University of Huddersfield researchers have identified a pair of metabolomic biomarkers for multiple sclerosis.

In a study published in Analytical Methods in September, the scientists used mass spec to compare the serum metabolomes of multiple sclerosis patients and controls and identified two markers, sphingosine and dihydrosphingosine, that were significantly downregulated in patients with MS.

The researchers are now in discussions with the UK's National Health Service about further studying the markers in a clinical environment, said Nick Powles, a chemist in Huddersfield's Innovative Physical Organic Solutions (IPOS) laboratory and senior author on the study. He added that he and his colleagues have also identified a number of other potential MS markers they hope to explore further.

In the study, the IPOS researchers looked at 40 samples: 10 from patients with multiple sclerosis, 10 from patients with neuropathic pain, 10 from patients with multiple sclerosis with neuropathic pain, and 10 health controls. Running these samples using liquid chromtography on an Agilent 1290 HPLC connected to an Agilent 6530 QTOF mass spectrometer, they identified 307 molecules, 25 of which differed between the control group and disease groups.

Of these 25, four were different only in the neuropathic pain group, 11 were altered in the MS with neuropathic pain group, and one was different only in the MS group. Searching the mass spec profile of this latter molecule against the Metlin database (a collection of metabolite mass spectra), the researchers identified sphingosine as a good match. They also identified the compound dihydrosphingosine as a match to one of the markers they found for distinguishing patients with MS with neuropathic pain from controls.

To confirm these identifications, they analyzed samples spiked with spingosine and dihydrosphingosine. They then measured the levels of these two compounds in a new set of MS patients and controls, looking at 15 patients with MS, 15 with MS and neuropathic pain, and 60 age- and gender-matched healthy controls. Levels of both markers were significantly lower in both sets of MS patients than controls.

Powles noted that previous research has indicated spingosine and dihydrosphingosine could be linked to MS. For instance, he said, the drug fingolimod (sold by Novartis as Gilenya), which is used to treat MS, is a sphingosine analog. The authors noted, as well, that the two molecules have been shown to be present at lower concentrations in the brain tissue of MS patients.

Multiple sclerosis is a challenging disease to diagnose with expensive approaches like MRI or invasive tests like spinal taps most commonly used. Were it to prove effective, a blood-based test like the one being investigated by the IPOS team could significantly simplify detection of the condition. A number of researchers and companies are exploring blood-based genomic, proteomic, and metabolomic markers for the disease. Last year, diagnostics firm IQuity launched its IsolateMS test, an RT-PCR-based assay that uses RNA expression patterns in blood to identify patients with MS.

Moving forward, the IPOS researchers will need to test the markers in larger cohorts with a wider range of immune conditions, Powles said. He noted that the other 20-plus molecules identified in the study could prove useful in adding discriminatory power to the panel. "There's at least another 20 that we haven't investigated yet that we could potentially use," he said, noting that the Analytical Methods study focused on spingosine and dihydrosphingosine in large part because they were easy to identify.

In addition to exploring other markers and testing them in larger patient cohorts and in actual clinical settings, Powles and his colleagues are also working to make the test more accurate. In particular, he said, they are hoping to find another circulating molecule that they can use as an internal standard for the test to account for the different conditions of the patients being tested.

"For instance," he said, "say you have a certain blood pressure. That means you have a certain blood concentration of various [circulating molecules]. Or, say you get dehydrated. Concentrations are then going to change slightly because you have less water in your body. And obviously that is all reflected in the test."

"So what we're thinking is that we need some internal standard that we can use so we're not looking at [absolute] concentration levels, we're looking at relative levels," he said.

Ultimately, Powles said, the goal would be to convert the test to a simple immunoassay akin to a pregnancy test, but he said he anticipated the researchers would continue to run it as a mass spec assay in the near-term. The IPOS lab is an Agilent Center of Excellence, and Powles and his colleagues are frequent collaborators with the company in both life science and pharma research and applied areas like food testing and agrochemical research, he said.