Damage to myelin caused by inflammatory oligodendrocyte cell destruction combined with axon degeneration are two of the signs of multiple sclerosis (MS). Most of the available medications for MS are approved for relapsing–remitting (RR) MS, for which they reduce relapse rate, MRI measures of inflammation, and the accumulation of disability.
But these medications are of little use in progressive multiple sclerosis, where axon degeneration following demyelination surpasses inflammation. Hence the push for development of new remyelination drugs to reverse the neurodegenerative damage seen in MS.
Now, researchers at Oregon Health & Science University have begun to apply a newly developed compound on a rare population of macaque monkeys who develop a disease that is similar to MS in humans.
“I think we’ll know in about a year if this is the exact right drug to try in human clinical trials. If it’s not, we know from the mouse studies that this approach can work. The question is, can this drug be adapted to bigger human brains,”
said senior author Larry Sherman, Ph.D., an OHSU professor in the Division of Neuroscience at the primate center.
Current research on the treatment of MS is directed at three major goals: preventing the development of new demyelinating lesions, protecting demyelinated axons from degeneration, and promoting remyelination.
Some of the research has been concentrated on identifying regenerative properties of existing drugs that might promote myelin repair. Promising medications include fingolimod, benztropine, an anticholinergic agent so far used to treat Parkinson’s disease, and Quetiapine fumarate, a schizophrenia medication.
The OHSU discovery culminates more than a decade of research following a 2005 breakthrough by Sherman’s lab.
In that study, scientists discovered that a molecule called hyaluronic acid, or HA, accumulates in the brains of patients with MS. Further, the scientists linked this accumulation of HA to the failure of cells called oligodendrocytes to mature.
Oligodendrocytes generate myelin.
Myelin, in turn, forms a protective sheath covering each nerve cell’s axon – the threadlike portion of a cell that transmits electrical signals between cells.
Damage to myelin is associated with MS, stroke, brain injuries, and certain forms of dementia such as Alzheimer’s disease. In addition, delay in myelination can affect infants born prematurely, leading to brain damage or cerebral palsy.
Investigating Hyaluronic Acid
Subsequent studies led by the Sherman lab showed that HA is broken down into small fragments in multiple sclerosis lesions by enzymes called hyaluronidases. In collaboration with Stephen Back, M.D., Ph.D., a professor of pediatrics in the OHSU School of Medicine, Sherman discovered that the fragments of HA generated by hyaluronidases send a signal to immature oligodendrocytes not to turn on their myelin genes.
That led researchers to explore how they might block hyaluronidase activity and promote remyelination.
For the past decade, an international team of researchers led by OHSU has been working to develop a compound that neutralizes the hyaluronidase in the brains of patients with MS and other neurodegenerative diseases, thereby reviving the ability of progenitor cells to mature into myelin-producing oligodendrocytes.
Inhibiting Oligodendrocyte Growth
The new study describes a modified flavonoid – a class of chemicals found in fruits and vegetables – that does just that.
The compound, called S3, reverses the effect of HA in constraining the growth of oligodendrocytes and promotes functional remyelination in mice. Lead author Weiping Su, Ph.D., senior scientist in the Sherman lab, dedicated years of intensive research to make the discovery.
“It’s not only showing that the myelin is coming back, but it’s causing the axons to fire at a much higher speed,” Sherman said. “That’s exactly what you want functionally.”
The next phase of research involves testing, and potentially refining, the compound in macaque monkeys who carry a naturally occurring version of MS called Japanese macaque encephalomyelitis. The condition, which causes clinical symptoms similar to multiple sclerosis in people, is the only spontaneously occurring MS-like disease in nonhuman primates in the world.
Keep in mind that this study was conducted in a mouse model of MS, not humans. While the underlying biological mechanisms are similar enough that it will probably contribute clues for an eventual human treatment, it is a long-term goal, and this study does not necessarily signal hope for a new miracle drug.
The mouse model is commonly used because their neurons function very similar to human neurons, however the biggest challenge to studying brain disorders is the blood brain barrier.
The BBB is not the same in mice and humans, so drugs that are successful in mouse trials often cannot reach the brain in humans and are ineffective once they reach human clinical trials.
Another difference in mouse and human brains is highlighted in a recent transcriptomics study that found gene expression differences between mouse and human brain cells.
Having said that, this kind of incremental basic research is valuable and the fact that a cure may still not yet be on the horizon is, of course, no reason to stop progressing and learning about this disease. David Kremer, Patrick Küry and Ranjan Dutta. Promoting remyelination in multiple sclerosis: Current drugs and future prospects. Multiple Sclerosis Journal 2015, Vol. 21(5) 541–549 DOI: 10.1177/ 1352458514566419  Back, Stephen & Tuohy, Therese & Chen, Hanqin & Wallingford, Nicholas & Craig, A & Struve, Jaime & Ling Luo, Ning & Banine, Fatima & Liu, Ying & Chang, Ansi & Trapp, Bruce & Bebo, Bruce & Rao, Mahendra & S Sherman, Larry. (2005). Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nature medicine. 11. 966-72. 10.1038/nm1279.  Preston, M. , Gong, X. , Su, W. , Matsumoto, S. G., Banine, F. , Winkler, C. , Foster, S. , Xing, R. , Struve, J. , Dean, J. , Baggenstoss, B. , Weigel, P. H., Montine, T. J., Back, S. A. and Sherman, L. S. (2013), Digestion products of the PH20 hyaluronidase inhibit remyelination. Ann Neurol, 73: 266-280. doi:10.1002/ana.23788  Su, W, Matsumoto, S, Banine, F, et al. A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination. Glia. 2019; 1– 17. https://doi.org/10.1002/glia.23715
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