(NIH) - 4/24/2015 - 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 on April 20, 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.
Source: National Institutes of Health