the mechanism of action of many multiple sclerosis treatments is
unknown, scientists at Bad Nauheim’s Max Planck Institute for Heart and
Lung Research and the University of Lübeck unlocked the mechanism for
dimethyl fumarate (DMF), a multiple sclerosis drug that just received
approval in Europe under the name Tecfidera. Dr. Nina Wettschureck’s and
Dr. Markus Schwaninger’s research groups discovered the reason for
immune function influence by DMF, which has also been used as a
successful treatment for psoriasis.
Simply stated by Dr. Schwaninger, “In mice [with a standard model of multiple
that don’t have the gene for the receptor called HCA2, DMF was unable
to prevent the signs of paralysis.” Wild type mice with multiple
sclerosis that were treated with DMF had significantly fewer problems
with motor function, according to Dr. Wettschureck.
words, DMF acts by blocking HCA2 receptor, a G protein-coupled membrane
receptor found on the the surface of neutrophil granulocytes, a specific
type of white blood cells. Activation of HCA2 receptor causes
granulocytes to infiltrate the central nervous system, where
auto-reactive immune cells damage neurons and cause multiple sclerosis.
“Our study has enabled us to provide the first evidence that DMF’s
protective effect is due to the HCA2 receptor. However, we are not
ruling out the possibility that there may also be other mechanisms,”
concluded Dr. Wettschureck.
“In animals treated with
DMF, the number of granulocytes that infiltrated the nervous system was
much lower than in untreated animals,” said Dr. Wettschureck, “In
animals without the HCA2 receptor, the number of invasive granulocytes
remained equally high despite treatment with DMF.” This suggests a
reason for why patients respond differently to DMF and for how treatment
may be custom-designed in the future: “It may be that individual
genetic differences influence the efficacy of DMF,” stated Dr.
Basic MS therapy to date generally
involved beta interferons or the active substance glatiramer acetate. In
both cases, the drug was administered by injections under the skin or
into the muscle, which is a cause of considerable discomfort and
annoyance to many patients.
By contrast, the active
substance dimethyl fumarate (DMF), approved in Europe for MS treatment
only a few weeks ago, brings a ray of hope to those affected since it
can be taken in tablet form. The efficacy of DMF in clinical studies was
at least comparable to that of the more established substances, while
its side effects were moderate by comparison.
has been in use for some twenty years as a successful treatment for
psoriasis, but little was known about how it influences immune function.
Scientists from Nina Wettschureck's research groups at the Max Planck
Institute for Heart and Lung Research in Bad Nauheim and Markus
Schwaninger from the Institute of Experimental and Clinical Pharmacology
and Toxicology at the University of Lübeck have explained significant
aspects of how DMF works.In their study, the researchers used a
standardised mouse model of multiple sclerosis, whereby drugs trigger an
autoimmune response, leading to characteristic reactions within days.
In this way, they induced neurological deficits comparable to those
observed in MS. "In the group we treated with DMF, the problems with
motor function were considerably lower than in the control group," says
The researchers uncovered the mode of
action by treating genetically modified mice in the same way. "In mice
that don't have the gene for the receptor called HCA2, DMF was unable to
prevent the signs of paralysis," explains Schwaninger. This means that
the HCA2 receptor must mediate the therapeutic effect of DMF.HCA2 is a
so-called G protein-coupled membrane receptor which occurs, among other
places, on a certain type of white blood cells, neutrophil granulocytes.
"In animals treated with DMF, the number of granulocytes that
infiltrated the nervous system was much lower than in untreated animals.
In animals without the HCA2 receptor, the number of invasive
granulocytes remained equally high despite treatment with DMF," stated
In other experiments involving cell
cultures, the scientists found that activation of the HCA2 receptor is
responsible for infiltration of the central nervous system by white
blood cells. DMF blocks this infiltration, thereby preventing the
associated inflammation. "Our study has enabled us to provide the first
evidence that DMF's protective effect is due to the HCA2 receptor.
However, we are not ruling out the possibility that there may also be
other mechanisms," observed Wettschureck.
As a next
step, the scientists want to find out why patients respond differently
to treatment with DMF. "It may be that individual genetic differences
influence the efficacy of DMF," states Schwaninger. Consequently, future
therapies could be specifically designed for individual patients, an
approach known as personalised medicine.
researchers also intend to search for additional substances that bind to
the HCA2 receptor. "Ideally, we would find a substance of comparable or
even greater efficacy, but with fewer side effects," says Wettschureck.
The colleagues in Bad Nauheim and Lübeck hope this will lead to the
development of novel therapeutic agents for MS with an improved profile
in terms of efficacy and adverse effects.