Cholesterol drugs may offer first inexpensive, easy therapy for CCM
LAKE CITY – In a finding that could save thousands of lives a year,
University of Utah School of Medicine researchers have shown that a
blood vessel disorder leading to unpredictable, sometimes fatal,
hemorrhagic strokes, seizures, paralysis or other problems is treatable
with the same statin drugs that millions of people take to control high
If the results of a study in mice are confirmed
in a pilot trial with people, statins could provide a safe, inexpensive
treatment for cerebral cavernous malformation (CCM), a disorder with no
known drug therapy, according to U of U cardiologist Dean Y. Li, M.D.,
Ph.D., director of the Molecular Medicine Program and corresponding
author of a study published Jan. 18 in
Nature Medicine online.
surgery or radiation treatment has been the only option for CCM
patients. But because of the risks in those operations, neurosurgeons
are reluctant to perform them unless the patient is in immediate
danger," Li said. "Our study proposes a potential strategy for a simple
drug therapy that could cost only a few dollars a month at a pharmacy.
However, our animal studies must first be evaluated in a pilot clinical
trial being initiated."
Kevin J. Whitehead, M.D., also a
cardiologist, assistant professor of internal medicine, and first
author of the study, now is recruiting 50 to 100 people diagnosed with
CCM to join a pilot trial of statins.
CCM is a disorder in
which blood vessels in the brain become dilated and weakened, and leak
blood, causing strokes, headaches, seizures or other problems.
Diagnosing CCM can be problematic. Some people are diagnosed after
experiencing symptoms and undergoing an MRI; others find out they have
CCM during an MRI for an unrelated problem. An estimated 25 percent of
people with CCM experience no symptoms and never know they have it. In
worst-case scenarios, "people don't know they have CCMs until they
suffer from an acute brain attack," Li said.
Connie Lee of the Angioma Alliance, "Cavernous angioma or cerebral
cavernous malformation is a common but little known illness that can
strike with devastating consequences for individuals in any stage of
life. The disease has affected the strongest among us, including
prominent athletes such as the Olympic superstar, Florence Griffith
Joyner, and the Tour De France champion, Alberto Contador. In its
hereditary form, it is especially prevalent in members of the original
Hispanic families that settled the American Southwest."
the precise number of people with CCM is not known, it's estimated up
to 0.5 percent of the U.S. population or about 1.5 million people may
have some form of CCM, according to Whitehead. "Statin therapy,
particularly, could benefit people who are genetically predisposed to
CCM," he said. "Of vital importance is the impact this research might
have on the large number of our Hispanic population in the Southwest
and Rocky Mountain West who carry a gene mutation, passed from common
ancestors, that predisposes them to CCM."
Whitehead and Li
suspect statins, such as Zocor, Lipitor, and similar drugs, treat CCM
by stabilizing blood vessels so they don't leak.
CCM can be
inherited genetically or occur sporadically. Three known genes have
been associated with genetic-related CCM, but the role of those genes,
Ccm1, Ccm2, and Ccm3, has been unclear. Whitehead and Li demonstrated
that without Ccm2, the endothelium, a thin, inner lining of cells that
forms a blood vessel's tubular passage for blood flow, does not form
properly. When that happens, blood vessels can become weak and dilated,
allowing them to leak.
In mice with two distinct mutations of
Ccm2, meaning the gene's function was knocked out, the researchers
observed increased activity in Rho, an enzyme that regulates
endothelium formation. Li and Whitehead theorized that increased Rho
activity in endothelial cells might lead to the blood vessel defects
seen in CCM patients. They tested their hypothesis by administering
simvastatin, which is known to inhibit Rho activity, to mouse models
with the Ccm2 mutations and saw that the drugs strengthened the damaged
blood vessels in the mice."
Eugene Golanov, M.D., Ph.D., a
program director at the National Institute of Neurological Disorders
and Stroke, part of the National Institutes of Health, said Li's and
Whitehead's study is an important work. "By attacking this disease from
many angles – including genetic, biochemical and pharmacological
approaches – Dr. Li's team has shed new light on the mechanism of the
disease and a potential drug therapy, " Golanov said. "Their success
illustrates the importance of encouraging teams of scientists and
physicians across institutions and disciplines to target familial
stroke diseases such as cerebral cavernous malformations."
Li's and Whitehead's
study was the first to show in a live animal model that any of the Ccm
genes, in this case Ccm2, is required for the endothelium. Physicians
and patients known to have familial CCM who are interested in
participating in the pilot trial of statins should contact Kevin
Whitehead, M.D., at the University of Utah School of Medicine (Kevin.firstname.lastname@example.org) or Connie Lee (clee@AngiomaAlliance.org)