Anti-Cancer Drug Prevents, Reverses
Cardiovascular Damage in Mouse Model of Premature Aging Disorder
An experimental anti-cancer drug can prevent — and even
reverse — potentially fatal cardiovascular damage in a mouse
model of progeria, a rare genetic disorder that causes the most
dramatic form of human premature aging, National Institutes of
Health (NIH) researchers reported today.
In a study published in the Oct. 6 early online edition of the
Proceedings of the National Academy of Sciences, a team led by
Francis S. Collins, M.D., Ph.D., of the National Human Genome Research
Institute (NHGRI), and Elizabeth G. Nabel, M.D., director of the
National Heart, Lung and Blood Institute (NHLBI), describes its
effort to use transgenic mice to identify and test potential therapies
for children with Hutchinson-Gilford progeria syndrome.
There currently are no treatments for progeria, which is estimated
to affect about one child in 4 million. At birth, children with
progeria appear normal. But soon growth slows, and the children
begin to show signs of accelerated aging, such as hair loss, wrinkled
skin and loss of body fat. The most lethal damage, however, occurs
within the children’s major blood vessels. The children develop
premature cardiovascular disease, which typically leads to death
from heart attack or stroke at about the age of 13.
Building upon its past experiments in cells and mice, the NIH-led
team examined the effects of the experimental cancer drug tipifarnib
in a strain of mice genetically engineered to develop cardiovascular
damage similar to that seen in progeria patients. Tipifarnib belongs
to a class of drugs known as farnesyltransferase inhibitors (FTIs),
which are being tested in people with myeloid leukemia, neurofibromatosis
and other conditions. The team had previously found that FTI drugs
could reverse structural abnormalities in skin cells taken from
progeria patients and grown in the laboratory.
"This approach worked much better than we thought it would.
Not only did this drug prevent these mice from developing cardiovascular
disease, it reversed damage in mice that already had disease," said
the study’s senior author, Dr. Collins, who is the former director
of NHGRI and who continues to conduct research as a special volunteer
in the Genome Technology Branch of NHGRI’s Division of Intramural
Researchers emphasized that more work needs to be done to determine
whether FTI drugs will reverse progeria-associated cardiovascular
disease in humans the same way they do in mice. In children suffering
from progeria, the cardiovascular disease process often remains
relatively stable until late in life, when it dramatically accelerates.
"If these drugs are found to have similar effects in children,
this could mark a major breakthrough for treating this devastating
disease," said NHLBI’s Dr. Nabel, who was a co-author of the study. "In
addition, these findings shed light on the potential role of FTI
drugs to treat other forms of coronary artery disease."
In 2007, researchers led by Mark Kieran, M.D., Ph.D., at the Dana-Farber
Cancer Institute in Boston launched a clinical trial of the FTI
drug lonafarnib in 28 progeria patients, ranging in age from 3
to 15, from 16 countries. Results of that study are not expected
for at least a year.
Earlier this year, in experiments involving a different type of
mouse model for progeria, a group of French and Spanish researchers
reported that a combination of statin and bisphosphonate drugs
slowed development of the visible symptoms of aging and extended
life spans in the animals. Both drugs act upon the same biological
pathway as FTI drugs.
While progeria affects only a few dozen children worldwide, efforts
aimed at untangling the biological roots of this rare disease may
prove valuable in understanding the human aging process in general. "What
we learn through studies of rare genetic disorders often has implications
for more common conditions," said NHGRI Scientific Director
Eric D. Green, M.D., Ph.D. "For example, a growing body of
evidence indicates that all people produce small amounts of the
mutant protein found in progeria patients, and that this protein
may play roles in aging or longevity."
In addition to NHGRI and NHLBI, the team that conducted the most
recent study included researchers from Emory University School
of Medicine, Atlanta and CVPath Institute, Inc., Gaithersburg,
For more information about progeria, go to http://www.genome.gov/11007255.
A high-resolution photograph contrasting the coronary arteries
of treated and untreated mice is available at http://www.genome.gov/pressDisplay.cfm?photoID=20132.
A high-resolution photograph of a child with progeria is available
A photograph of cells from progeria patients is available at http://www.genome.gov/pressDisplay.cfm?photoID=37.
NHLBI plans, conducts, and supports research related to the causes,
prevention, diagnosis, and treatment of heart, blood vessel, lung,
and blood diseases; and sleep disorders. The Institute also administers
national health education campaigns on women and heart disease,
healthy weight for children, and other topics. NHLBI press releases
and other materials are available online at www.nhlbi.nih.gov.
NHGRI is one of 27 institutes and centers at the NIH, an agency
of the Department of Health and Human Services. The NHGRI Division
of Intramural Research develops and implements technology to understand,
diagnose and treat genomic and genetic diseases. Additional information
about NHGRI can be found at its Web site, www.genome.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.