New model of nerve fibers could speed path for MS treatments
Soft, flexible platform designed to test myelin repair
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A new model of nerve fibers aims to more closely replicate human axons. (Image from iStock)
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A new soft, flexible nerve fiber model helps screen MS drugs.
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Stiffer models could be misleading about drug efficacy.
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This realistic model improves drug validation, potentially accelerating MS treatments.
A new model of nerve fibers may serve as a platform to screen for experimental treatments that can promote myelin repair in multiple sclerosis (MS), a study showed.
The model is made of soft micropillars around which myelin-producing cells can wrap myelin. Researchers found that some drugs tended to be less effective in these softer structures than in previous models made of hard materials, which may explain why drugs that show promise in the lab ultimately fail in clinical trials.
“We hope this [model] can lead to more reliable validation of potential drugs before they reach patients in clinical trials,” Emad Moeendarbary, PhD, co-author of the study and a professor at University College London, said in a university news story.
The study, “Tunable hydrogel-based micropillar arrays for myelination studies,” was published in Nature Methods.
Myelin repair has been an elusive goal
In MS, inflammation in the brain and spinal cord damages myelin, a fatty substance that wraps around nerve fibers (axons), protecting them and helping them transmit electrical signals.
Available MS treatments can dampen inflammation, but so far, no therapy has been definitively proven to promote myelin repair in people with MS. In theory, drugs that repair myelin could help not only slow MS progression, but also reverse the disease.
Researchers studying myelin-targeting therapies often rely on models in which oligodendrocytes, the specialized cells that make myelin in the brain and spinal cord, are grown alongside artificial nerve fibers. In these models, oligodendrocytes wrap myelin around the fibers, and researchers can test whether the activity of these cells is altered by experimental treatments.
A major limitation has been that the artificial nerve fibers are usually made from materials such as plastic. While relatively easy to work with, these materials are stiff and lack the texture of real nerve fibers.
“To stop MS, we need therapies that repair myelin,” Moeendarbary said. “Promising drug candidates in the past have failed when tested in human patients. One factor might be that laboratory models do not replicate the basic physical properties of the human brain.”
Moeendarbary and colleagues described a new model that uses artificial nerve fibers made from flexible, jelly-like materials called hydrogels.
“Hydrogel is a close mimic of living cells,” Moeendarbary said. “Like an actual cell, it is made mostly of water and is porous. But to fabricate a soft hydrogel at such a small scale is not an easy task.”
The work “involved five years of careful experimentation and refinement,” Moeendarbary said, and “the result is a model that is as close as possible to real nerve fibers.”
Through a battery of tests, the researchers demonstrated that their new model could serve as a reliable platform for measuring myelination (myelin production) from oligodendrocytes. This shows that the model “could enable efficient, high-throughput myelination screening,” they said.
The scientists noted that their model is compatible with human oligodendrocytes, which they said is “a critical step forward in translational relevance, as most prior systems rely on rodent cells.”
The system was used to test several experimental compounds shown in previous lab studies to boost myelin repair. One such compound is clemastine, an antihistamine that has been tested in MS trials for myelin repair but has shown limited efficacy, with some studies suggesting it may even worsen MS progression.
The researchers found that clemastine and similar compounds effectively improved myelin production when oligodendrocytes were grown alongside hard nerve fiber models used in prior studies. But with the more flexible pillars, these medications were substantially less potent.
These findings indicate that the mechanical properties of nerve fibers influence myelin repair, the researchers noted, highlighting the importance of their platform for screening drugs that could be effective in people.
“Our work suggests that commonly used rigid models, hundreds of times stiffer than real axons, can generate misleading drug hits,” Moeendarbary said. “We believe that our more life-like model can be used as a more robust early test of drug candidates and as a platform to discover new drugs.”
