Two drugs already on the market — an antifungal and a steroid — may potentially take on new roles as treatments for multiple sclerosis. According to a study published in Nature today, researchers discovered that these drugs may activate stem cells in the brain to stimulate myelin producing cells and repair white matter, which is damaged in multiple sclerosis. The study was partially funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
Specialized cells called oligodendrocytes lay down multiple layers of a fatty white substance known as myelin around axons, the long “wires” that connect brain cells. Myelin acts as an insulator and enables fast communication between brain cells. In multiple sclerosis there is breakdown of myelin and this deterioration leads to muscle weakness, numbness and problems with vision, coordination and balance.
“To replace damaged cells, the scientific field has focused on direct transplantation of stem cell-derived tissues for regenerative medicine, and that approach is likely to provide enormous benefit down the road. We asked if we could find a faster and less invasive approach by using drugs to activate native nervous system stem cells and direct them to form new myelin. Our ultimate goal was to enhance the body’s ability to repair itself,” said Paul J. Tesar, Ph.D., associate professor at Case Western Reserve School of Medicine in Cleveland, and senior author of the study.
It is unknown how myelin-producing cells are damaged, but research suggests they may be targeted by malfunctioning immune cells and that multiple sclerosis may start as an autoimmune disorder. Current therapies for multiple sclerosis include anti-inflammatory drugs, which help prevent the episodic relapses common in multiple sclerosis, but are less effective at preventing long-term disability. Scientists believe that therapies that promote myelin repair might improve neurologic disability in people with multiple sclerosis.
Adult brains contain oligodendrocyte progenitor cells (OPCs), which are stem cells that generate myelin-producing cells. OPCs are found to multiply in the brains of multiple sclerosis patients as if to respond to myelin damage, but for unknown reasons they are not effective in restoring white matter. In the current study, Dr. Tesar wanted to see if drugs already approved for other uses were able to stimulate OPCs to increase myelination.
OPCs have been difficult to isolate and study, but Dr. Tesar and his colleagues, in collaboration with Robert Miller, Ph.D., professor at George Washington University School of Medicine and Health Sciences in Washington, D.C., developed a novel method to investigate these cells in a petri dish. Using this technique, they were able to quickly test the effects of hundreds of drugs on the stem cells.
The compounds screened in this study were obtained from a drug library maintained by NIH’s National Center for Advancing Translational Sciences (NCATS). All are approved for use in humans. NCATS and Dr. Tesar have an ongoing collaboration and plan to expand the library of drugs screened against OPCs in the near future to identify other promising compounds.
Dr. Tesar’s team found that two compounds in particular, miconazole (an antifungal) and clobetasol (a steroid), stimulated mouse and human OPCs into generating myelin-producing cells.
Next, they examined whether the drugs, when injected into a mouse model of multiple sclerosis, could improve re-myelination. They found that both drugs were effective in activating OPCs to enhance myelination and reverse paralysis. As a result, almost all of the animals regained the use of their hind limbs. They also found that the drugs acted through two very different molecular mechanisms.
“The ability to activate white matter cells in the brain, as shown in this study, opens up an exciting new avenue of therapy development for myelin disorders such as multiple sclerosis,” said Ursula Utz, Ph.D., program director at the NINDS.
Dr. Tesar and his colleagues caution that more research is needed before miconazole and clobetasol can be tested in multiple sclerosis clinical trials. They are currently approved for use as creams or powders on the surfaces of the body but their safety administered in other forms, such as injections, in humans is unknown.
“Off-label use of the current forms of these drugs is more likely to increase other health concerns than alleviate multiple sclerosis symptoms. We are working tirelessly to ready a safe and effective drug for clinical use,” Dr. Tesar said.
This work was supported by the NINDS (NS085246, NS030800, NS026543), the New York Stem Cell Foundation and the Myelin Repair Foundation, New York City.
The NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.
The National Center for Advancing Translational Sciences is a distinctly different entity in the research ecosystem. Rather than targeting a particular disease or fundamental science, NCATS focuses on what is common across diseases and the translational process. The Center emphasizes innovation and deliverables, relying on the power of data and new technologies to develop, demonstrate and disseminate advancements in translational science that bring about tangible improvements in human health. For more information, visit http://www.ncats.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Najm et al. “Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo,” Nature, April 20, 2015.
Our review team had a lively debate as to the extent to which this National Institutes of Health news release exaggerates the findings of the study it reports on. We agreed that the release waits far too long to warn readers that this exciting study of potential multiple sclerosis drugs was conducted in petri dishes and mice. One has to read through more than half of the release before that crucial caveat is introduced. But we had mixed opinions about the headline, “Drugs that activate brain stem cells may reverse multiple sclerosis.” Some of us felt this was misleading because readers would assume the release is talking about human disease, and there’s nothing in the release or the underlying study to support a “reversal” of disease in humans. The opposing view is that the headline accurately reflects what happened in the study in mice and is therefore not an exaggeration. According to this view, the release is deficient mainly because it failed to qualify that the findings were from mice in a timely manner (ideally the first paragraph), but not because of the headline. We welcome reader perspectives on this debate in the comments.
The lackluster performance of the pharmaceutical industry in developing new treatments has led to coordinated efforts to repurpose existing drugs for new uses. The research highlighted in this NIH news release is important because it represents one of the earliest examples for this new form of drug development. Multiple sclerosis can be a devastating disease causing significant dysfunction and early death in some patients. Treatments at the moment consist of drugs that target the immune system. While effective, they come with a host of side effects and are very costly. The approach highlighted here provides a potentially new avenue of attack: promoting myelin repair. With that said, this is very early in the game and the drugs — clobetasol and miconazole — have only been shown to work in the test tube and in a mouse model. As we have said on many occasions, success in the mouse model is just that: success in the mouse model.
While one could argue that we should give the release a pass given the early stage of the research, the drugs discussed are commercially available and it would have been easy to provide cost information.
The release provides insufficient detail regarding what occurred in this study and the outcomes that were reported. The release states that “both drugs were effective in activating OPCs to enhance myelination and reverse paralysis. As a result, almost all of the animals regained the use of their hind limbs.” But how many animals were studied, and how many of them regained use of their limbs? Was there total resolution of symptoms or only partial resolution, and how was this measured? The release never quantifies these results.
Dr. Tesar provides a cautionary note related to the potential harms of this approach; “Off-label use of the current forms of these drugs is more likely to increase other health concerns than alleviate multiple sclerosis symptoms.” Given the stage of research, we think this is sufficient to rate this criterion as satisfactory
Our major concern with the description of evidence is that the release waits too long to inform readers that these results were obtained in petri dishes and mice. We have to read more than halfway through the release to learn of this crucial caveat. We also had concerns about the headline as noted above in the Review Summary section.
To its credit, the news release does provide an important cautionary statement: “…more research is needed before miconazole and clobetasol can be tested in multiple sclerosis clinical trials.”
But this statement, coming late in the release, is too little to counterbalance the enthusiasm generated earlier in the release based on an incomplete and possibly misleading description of the evidence.
No disease mongering is evident.
We are told up front that the study was funded by a division within the National Institutes of Health, and there is no apparent conflict of interest according to the paper.
The news release earns a Satisfactory rating by speaking to the current treatments that are available: “Current therapies for multiple sclerosis include anti-inflammatory drugs, which help prevent the episodic relapses common in multiple sclerosis, but are less effective at preventing long-term disability.”
To earn extra credit here, the release could have provided a comment about other research into improving myelin production. This includes ongoing clinical trials being conducted by Biogen and others targeting myelin production in MS.
The story makes it clear that the two drugs highlighted (clobetasol and miconazole) are available and adds the important precatuionary note, “…are currently approved for use as creams or powders on the surfaces of the body but their safety administered in other forms, such as injections, in humans is unknown.”
This is indeed first of its kind research and that is appropriately noted in the news release.
With the possible exception of the headline — an issue we’ve already addressed elsewhere in this review — no hyperbole is evident.