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Sunday, May 31, 2015

Two Topical Drugs Show Promise Against Multiple Sclerosis

By: Megan Brooks  - May 01, 2015


Research designed to repurpose approved drugs for new uses has turned up two drugs that may take on new roles as novel treatments for multiple sclerosis (MS).
A team of US scientists has found that the antifungal miconazole and the steroid clobetasol stimulate mouse and human oligodendrocyte progenitor cells (OPCs) into generating myelin-producing cells in culture.
Systemic delivery of the drugs significantly increased the number of new myelinating oligodendrocytes and enhanced 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 MS led to "striking" reversal of disease severity, with almost all of the animals regaining the use of their hind limbs, they note.
The results were published online April 20 as a letter in Nature.
A Paradigm Shift
Immune response assays suggest that miconazole functions directly as a remyelinating drug with no effect on the immune system, while clobetasol is a potent immunosuppressant as well as a remyelinating agent, the authors note. Mechanistic studies hint that miconazole and clobetasol function in OPCs through mitogen-activated protein kinase and glucocorticoid receptor signaling, respectively.
"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," Paul J. Tesar, PhD, co-senior author, from Case Western Reserve School of Medicine in Cleveland, Ohio, commented in a news release.
"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," Dr Tesar said.
The ability of miconazole and clobetasol to enhance the regenerative capacity of stem cells in the adult nervous system "truly represents a paradigm shift in how we think about restoring function to multiple sclerosis patients," said co-senior author Robert H. Miller, PhD, a member of the neurosciences faculty at Case Western Reserve.
The researchers hit on miconazole and clobetasol as potential MS treatments by screening hundreds of approved compounds in a drug library maintained by the National Center for Advancing Translational Sciences, part of the National Institutes of Health. Dr Tesar and colleagues plan to expand the library of drugs screened against OPCs in the near future to identify other promising compounds.
This research "opens up an exciting new avenue of therapy development for myelin disorders such as multiple sclerosis," Ursula Utz, PhD, program director at the National Institute of Neurological Disorders and Stroke, said in a news release.
Dr Tesar and his colleagues caution that the work is preliminary and much more research is needed before miconazole and clobetasol can be tested in MS clinical trials. Both agents are currently only approved for topical use, and their safety when administered in other forms in humans is unknown.
The researchers conclude that "significant optimization of dosing, delivery, and potentially chemical structure will be required to enhance the on-target pharmacology in OPCs while diminishing any potential off-target side effects. However, the ability of miconazole and clobetasol to cross the blood–brain barrier raises the exciting possibility that these drugs, or modified derivatives, could advance into clinical trials for the currently untreatable chronic progressive phase of MS."
This research was supported by the National Institutes of Health, New York Stem Cell Foundation, Myelin Repair Foundation, and the Mt. Sinai Health Care Foundation. Philanthropic support also came from the Goodman Trust; Cleveland Foundation; and the families of Bruce and Brenda Goodman, Lionel and Irmgard Long, and Albert and Norma Geller. The authors have disclosed no relevant financial relationships.
Nature. Published online April 20, 2015. Abstract



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