An American mother’s hunch might result in new
treatments for patients who can’t tolerate
conventional cholesterol-lowering drugs.
An American mother with twin daughters with a rare
incurable disease may seem like an unlikely partner
in cholesterol research. But when Chris Hempel read
about the role of cholesterol crystals in heart
disease in 2010, she immediately thought of her
daughters Addison and Cassidy, whose cells are
unable to get rid of cholesterol.
Perhaps the experimental drug that was being used to
treat her girls could also treat people with heart
disease? She contacted Eicke Latz, the University of
Bonn researcher behind the study, and suggested he
look into the idea. Latz is also an assistant
professor at NTNU’s Centre of Molecular Inflammation
Research (CEMIR).
Six years later, Hempel’s hunch has been confirmed:
in a paper published in early April in Science
Translational Medicine, Latz and an international
team reported that the drug cyclodextrin can
dissolve cholesterol crystals so they can be
excreted by the body.
The drug also changes the way the body’s immune
system responds to the presence of cholesterol
crystals, reducing inflammation in artery walls.
Hempel is listed as one of the co-authors.
Although there already are different medicines on
the market that can treat high cholesterol, some
people experience side effects from these drugs.
Cyclodextrin thus offers a potential new therapy for
cardiovascular disease, Latz and his colleagues say.
Your body needs (and makes) cholesterol in small
amounts, but too much cholesterol can lead to
hardening of the arteries, or atherosclerosis.
Atherosclerosis is when artery walls are coated in
plaque, which is made of a mix of cholesterol,
calcium and other substances. The plaque makes
arteries less flexible and causes them to narrow,
thereby reducing blood flow. Eventually the arteries
may be completely closed off by a blood clot, which
can cause a stroke or heart attack.
In the 2010 study that caught Hempel’s attention,
researchers reported how cholesterol crystals were
found to cause inflammation in arteries, which then
led to atherosclerosis. When Latz and his
collaborators, including Terje Espevik, head of
CEMIR, heard Hempel’s idea to test cyclodextrin,
they “jumped on it,” Espevik said.
The researchers tested cyclodextrin in mice that
were fed a cholesterol-rich diet and that were prone
to develop atherosclerosis.
“We saw that cyclodextrin prevented plaque
formation. It even reduced the existing plaque the
mice had in their arteries,” Espevik said.
To see if the drug would also work in human tissue,
CEMIR postdoc Siril Bakke was given access to a
biobank, collected by Bente Halvorsen from the
University of Oslo, OUS Rikshospitalet, with plaque
biopsies taken from human carotid arteries. When
Bakke examined biopsies of plaques treated with
cyclodextrin, she found that the cholesterol was
removed from the plaques. The cells in the plaque
were also reprogrammed so they were in a reduced
inflammatory state.
Another positive effect of cyclodextrin was that it
reprogrammed macrophages, immune cells in the body
that remove foreign or bad substances, Espevik said.
“What cyclodextrin did was to reprogram the
macrophage so it didn’t create such a big
inflammatory response,” Espevik said. That meant the
macrophage could soak up excess cholesterol and
remove it, while reducing the inflammation in the
artery walls and thus reducing the likelihood of
causing a plaque to form.
That means that cyclodextrin works via two
mechanisms, Espevik said. The first is to dissolve
cholesterol crystals so the body can excrete them,
and the second is to reduce the inflammatory
response in artery walls when macrophages soak up
cholesterol crystals.
The findings were so positive that the research team
is now hoping to find funding and an industrial
partner to conduct clinical trials in humans,
Espevik said.
Latz estimates it will take approximately EUR 1
million to do the trials. One potential drawback is
also one of the most positive aspects of
cyclodextrin: the substance, which is a type of
sugar, has already been approved by the US Food and
Drug Administration for use in humans. But because
it has been in existence for some time, it cannot be
patented. That makes it harder to get a drug company
interested in developing cyclodextrin to treat heart
disease, but it also will make it easier to get the
drug approved to treat heart disease if the clinic
trials support the research findings.
In addition to Latz and Espevik and their colleagues
at the University of Bonn and NTNU, scientists from
the University of Oslo/OUS Rikshospitalet and from
Australia, the USA, Denmark and Sweden contributed
to the research.
See
also:
Cholesterol is far better than its bad reputation,
good HDL cholesterol can actually limit
atherosclerosis (2016-04-27)
Link...
For more information
Cyclodextrin promotes atherosclerosis regression via
macrophage reprogramming.
Sebastian Zimmer, Alena Grebe, Siril S. Bakke,
Niklas Bode, Bente Halvorsen, Thomas Ulas, Mona
Skjelland, Dominic De Nardo, Larisa I. Labzin, Anja
Kerksiek, Chris Hempel, Michael T. Heneka, Victoria
Hawxhurst, Michael L. Fitzgerald, Jonel Trebicka,
Ingemar Björkhem, Jan-Åke Gustafsson, Marit
Westerterp, Alan R. Tall, Samuel D. Wright, Terje
Espevik, Joachim L. Schultze, Georg Nickenig, Dieter
Lütjohann and Eicke Latz.
Science Translational Medicine 06 Apr 2016: Vol. 8,
Issue 333, pp. 333ra50
DOI: 10.1126/scitranslmed.aad6100
Link...
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