Simple Amino Sugar May Be Blood Biomarker, Treatment for Progressive MS
Markedly low levels of a simple amino sugar called N-acetylglucosamine (GlcNAc) were found in the bloodstream of people with progressive forms of multiple sclerosis (MS) and correlated with greater disease severity and disability, a study reported.
These findings support GlcNAc as a potential biomarker for more severe forms of MS.
A recently completed Phase 1 trial tested the safety of GlcNAc at specific doses. If found to be safe, researchers hope to conduct further clinical studies to evaluate GlcNAc as a potential MS therapy, and one that might promote myelin repair.
The study, “Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration,” was published in the journal JAMA Neurology.
MS is characterized by recurrent episodes of neurologic symptoms resulting from the inflammatory damage to the myelin sheath, which wraps around nerve fibers and enhances electrical signals between nerve cells.
In the relapsing-remitting form of MS (RRMS), periods of symptom worsening are followed by a restoration of normal function. RRMS typically converts to the more severe secondary progressive MS (SPMS) over about 20 years. In primary progressive MS (PPMS), patients experience steady neurodegeneration from the onset of the first symptoms.
Progressive forms of MS are indicated by continuous inflammation, failure to generate new myelin, and progressive nerve degeneration, causing irreversible disability.
“In progressive MS, neurodegenerative processes steadily multiply and cause more and more neurons in the brain and spinal cord to die,” Alexander Brandt, MD, the study’s lead author and an associate professor of neurology at the University of California, (UC) Irvine, said in a press release. “However, we still do not know what exactly causes this disease variant.”
After proteins are synthesized, some are modified by adding complex sugars (N-glycans) in a process known as glycosylation, creating so-called glycoproteins. Some of these glycoproteins are highly branched with N-glycans, and play key roles in cell growth and signaling. An essential precursor in this process is GlcNAc, a common sugar and part of a regular diet.
Studies in mice suggest that reduced N-glycan branching promotes inflammatory myelin damage and blocks myelin repair. GlcNAc given as an oral supplement to MS mouse models was found to halt inflammatory responses, drive myelin repair, and ameliorate disease features.
“[We] observed in the mouse experiments that N-acetylglucosamine activates myelin progenitor cells, thus promoting both primary myelination and the repair of damaged myelin,” Brandt said.
Based on these findings, Brandt and colleagues at the Experimental and Clinical Research Center (ECRC) in Berlin, with collaborators at UC Irvine and the University of Toronto, wondered if the levels of GlcNAc in the bloodstream of people with MS were altered.
To find out, the team analyzed blood samples collected from MS patients in two phases — a discovery study at Irvine, followed by a confirmation study in Berlin.
Blood levels of GlcNAc were detected using a sensitive technique known as liquid chromatography–tandem mass spectroscopy (LC-MS/MS). As this method does not separate GlcNAc from related molecules called N-acetylgalactosamine (GalNAc) and N-acetylmannosamine (ManNAc), results were reported as HexNAc levels. Tests confirmed that HexNAc — using the spectroscopy technique — accurately tracked GlcNAc levels in human blood serum.
The discovery group included 54 MS patients: 33 with RRMS (25 women and eight men) and 21 with progressive MS (14 women and seven men). A control group of 66 age- and sex-matched healthy people were included as a comparison. In the control group, HexNAc concentration increased with age, but there was no difference between men and women.
After adjusting for age, RRMS patients were seen to have slightly lower-than-usual HexNAc levels, with a mean concentration of 682 nanomolar (nM) compared with 710 nM for controls. However, those with progressive MS had markedly reduced HexNAc levels — a mean of 548 nM — compared with both controls and RRMS participants.
“We studied 120 subjects from Irvine and were able to show that, in this particularly severe form of the disease [progressive MS], there are significantly lower concentrations of N-acetylglucosamine in the blood serum than there are in healthy people or patients with relapsing-remitting MS,” Brandt said.
HexNAc levels were not associated with prescribed treatments among all MS patients. Further statistical calculations found HexNAc levels distinguished between RRMS and PMS with an accuracy of 73.6%.
The confirmation study involved 180 patients: 125 with RRMS (83 women and 42 men) and 55 with progressive MS (22 women and 33 men). Here again, HexNAc levels were significantly lower in those with progressive MS patients (mean of 405 nM) compared with RRMS patients (mean of 709 nM).
This difference discriminated between RRMS and progressive MS with an accuracy of 90.5%, “which compares favorably with other well-established biomarkers,” the researchers wrote.
A comparison of those with PPMS and SPMS found similarly low HexNAc levels. These results were not affected by fasting and non-fasting blood samples.
Applying results from the confirmation study, researchers determined that lower HexNAc levels were significantly associated with greater disease severity as assessed by higher Expanded Disability Status Scale (EDSS) scores, as well as worse physical functioning, measured by the MS functional composite (MSFC) score, comprising a series of function tests.
No correlation existed between lower HexNAc levels and time since diagnosis.
With MRI scans, lower HexNAc concentrations also associated with reduced white matter volume (regions containing myelin), while whole-brain volume and gray matter volume did not significantly link with HexNAc. Additional tests showed lower HexNAc levels associated with more severe degeneration of nerve fibers in the retina of the eyes.
Finally, patients with low HexNAc levels showed a more significant decrease in brain volume than did those with high HexNAc levels, after adjusting for age and sex.
“Together, these data are consistent and reveal the association of low serum HexNAc levels with both clinical disability and multiple measures of neurodegeneration in MS,” the researchers wrote.
In this study from Berlin, “we also found that low serum levels of GlcNAc are associated with the development of the progressive form of the disease, clinical disability and neurodegeneration,” said Michael Demetriou, MD, PhD, the study’s senior author and a professor of neurology with an MS specialty at UC Irvine.
“This opens up potential new avenues for identifying, at an early stage, which patients are at higher risk of progressive MS and adjusting their treatment accordingly,” Demetriou said.
“Our hope is that we can use GlcNAc and the associated glycosylation mechanism to promote myelin repair and thus reduce neurodegeneration,” Brandt said.
“An initial, as-yet-unpublished phase I trial has just been completed with around 30 subjects, where the scientists investigated the safety of taking GlcNAc in certain doses. If it is shown to be safe, the scientists hope to be able to conduct further studies into this simple sugar’s possible efficacy as an MS therapy.”