NIH-funded study identifies over-the-counter compounds that may replace damaged cells.
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.
Research: This work was supported by the NINDS (NS085246, NS030800, NS026543), the New York Stem Cell Foundation and the Myelin Repair Foundation, New York City.
Source: Barbara McMakin – NINDS/NIH
Image Credit: Image courtesy of Case Western Reserve University; Illustrator: Megan Kern
Original Research: Abstract for “Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo” by Fadi J. Najm, Mayur Madhavan, Anita Zaremba, Elizabeth Shick, Robert T. Karl, Daniel C. Factor, Tyler E. Miller, Zachary S. Nevin, Christopher Kantor, Alex Sargent, Kevin L. Quick, Daniela M. Schlatzer, Hong Tang, Ruben Papoian, Kyle R. Brimacombe, Min Shen, Matthew B. Boxer, Ajit Jadhav, Andrew P. Robinson, Joseph R. Podojil, Stephen D. Miller, Robert H. Miller and Paul J. Tesar in Nature. Published online April 20 2015 doi:10.1038/nature14335
Abstract
Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo
Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes1. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention2. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells3, 4, 5. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.
“Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo” by Fadi J. Najm, Mayur Madhavan, Anita Zaremba, Elizabeth Shick, Robert T. Karl, Daniel C. Factor, Tyler E. Miller, Zachary S. Nevin, Christopher Kantor, Alex Sargent, Kevin L. Quick, Daniela M. Schlatzer, Hong Tang, Ruben Papoian, Kyle R. Brimacombe, Min Shen, Matthew B. Boxer, Ajit Jadhav, Andrew P. Robinson, Joseph R. Podojil, Stephen D. Miller, Robert H. Miller and Paul J. Tesar in Nature. Published online April 20 2015 doi:10.1038/nature14335
