Common Blood Pressure Drug Reduces Progressive
Muscle Degeneration in Mice
Scientists supported in part by the National Institutes of Health’s
National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS) and National Institute of Neurological Disorders and Stroke
(NINDS) have found that that the commonly prescribed blood pressure
medication losartan improves muscle regeneration and repair in
a mouse model of Duchenne muscular dystrophy (DMD), a devastating
disease characterized by rapid progression of muscle degeneration
in boys and young men. The research is based on similarities in
the mechanism of DMD and another rare disease — Marfan syndrome — and
the discovery that losartan is effective in blocking the key mechanism
in animal models of both diseases. Further studies of the drug,
scientists emphasize, are needed to assess its value in patients.
Marfan syndrome is a heritable connective tissue disorder affecting
many organ systems, resulting in dislocation of the lens of the
eye; progressive dilation of the aorta, which puts the aorta at
risk of rupture; and small, weak muscles, says Harry C. Dietz,
M.D., an author of the study in the February 2007 edition of Nature
Medicine. Until recent years, scientists believed that Marfan
syndrome was caused by weakness of tissues, says Dr. Dietz, the
Victor A. McKusick professor of genetics in the McKusick-Nathans
Institute of Genetic Medicine at the Johns Hopkins University School
of Medicine and director of the William S. Smilow Center for Marfan
Syndrome Research. But research by Dr. Dietz and his colleagues,
and funded by the National Heart, Lung, and Blood Institute, NIAMS
and others, has shown that the disease is the result of excessive
activity of a growth factor called TGF-beta in the muscles. “We
found that muscles were abnormal; they had very small fibers and
excess fibrosis — excessive connective tissue, or scarring — between
the fibers. What we learned was that high TGF-beta levels were
preventing a process called muscle regeneration.”
Normally, when a person damages their muscle or when they exercise
and send a signal to the muscle to get bigger, the muscle is able
to mobilize a population of muscle stem cells that proliferate
and then fuse to each other and to damaged muscle fibers to rapidly
accomplish muscle repair or muscle growth. In the presence of too
much TGF-beta, however, the cells simply do not get the signal
to accomplish this regenerative process, says Dr. Dietz. “We learned
that simply blocking TGF-beta in a mouse model of Marfan syndrome
could rescue muscle regeneration, normal architecture and muscle
function.”
Previous studies have demonstrated that the muscles of dystrophic
mice lose their ability to repair and regenerate efficiently, and
as in the human, the muscle tissue is progressively replaced by
scar tissue. Knowing that the same phenomenon occurred in Marfan
syndrome, Ronald D. Cohn, M.D., assistant professor of pediatrics
and neurology at Johns Hopkins’ McKusick-Nathans Institute of Genetic
Medicine, and Dr. Dietz and their colleagues tried to see if they
could extrapolate findings from the Marfan syndrome mouse model
to a mouse model of DMD. Their research paid off. They were able
to find evidence that excessive TGF-beta had a role in limiting
muscle regeneration in response to damage in DMD as well. When
the researchers gave the mice losartan to inhibit TGF-beta, they
showed that the muscle was able to regenerate and repair much more
efficiently. What’s more, when they treated the mice with the drug
over a period of time, the entire disease was attenuated, says
Dr. Cohn. “Here we had two completely different myopathies — muscle
diseases — that seemed to show a common pathway, which inhibits
the repair process of skeletal muscle.”
Losartan, a frequently prescribed and well-tolerated drug in humans,
works to reduce high blood pressure by blocking a molecule called
angiotensin II, which has been found not only to regulate blood
pressure but also to work against TGF-beta by a number of mechanisms.
Now that the drug has proven useful in mouse models of the two
diseases, the next step is to test them in people with the diseases.
A clinical trial of losartan for Marfan syndrome is scheduled to
begin later this month. Researchers are in the process of organizing
a clinical trial for DMD; patient recruitment is not yet underway.
If the drug proves useful in humans, as it has in mouse models,
it will represent a huge advance in the treatment of both diseases.
Current treatment for DMD is steroids. For many people with DMD,
steroids seem to bring improvement in muscle function, but that
improvement is offset by the drugs’ side effects, and the effects
are short-lived in some patients. In long-term treatment of mice
with losartan, however, the researchers have seen a sustained significant
improvement in muscle function. In fact, at about a year of age — which
would be equivalent to middle age in a person — the mice
with DMD actually had muscle function that was indistinguishable
from a normal mouse, says Dr. Dietz. “So I think that it has the
strong potential to not only have a more enduring effect, but also
to have a more profound effect on maintenance of muscle function” he
says. Losartan’s safety profile is also more favorable than that
of steroids. In 20 years of use in all human age groups, it has
shown a “remarkable tolerance profile,” he says. The most common
side effect of the drug — low blood pressure — can
usually be managed by simply lowering the dose of the drug, says
Dr. Cohn.
While much prior work in Marfan syndrome and DMD has been focused
on trying to replace the product of genes (for Marfan syndrome
a deficient protein called fibrillin-1; for DMD, a protein called
dystrophin), Dr. Dietz says this new research is reflective of
an emerging shift in attitude: to treat the disease as well as
possible with what is available now. “Right now, we don’t have
the technology to replace the deficient gene product to cure the
disease, but we might have the technology to prevent other secondary
events that contribute to the disease process,” he says. “In essence,
we are focusing on the low-hanging fruit that we can currently
address and that will have the strong potential to improve the
length and quality of life while we are tackling some of the obstacles
for a cure at the current time.”
NIAMS Director Stephen I. Katz, M.D., Ph.D., is cautiously optimistic
about the findings. “This treatment in mice is derived from knowledge
of the diseases’ mechanisms,” he says. “It has been shown to be
highly effective in mouse models. But we need to do clinical studies
first. If they are successful, this therapy has the potential to
help many people with devastating diseases for which there has
really been no good treatment.”
Pat Furlong, president and CEO of Parent Project Muscular Dystrophy,
adds a similar perspective. “The success of losartan in the mouse
model of Duchenne muscular dystrophy has been received with great
enthusiasm. Researchers and physicians who care for children with
DMD recognize the excitement as well as the sense of urgency within
the DMD community. Many parents are urging their primary care physicians
to agree to add losartan to their son’s current regimen. While
this approach is understandable, there is concern that extensive
off-label use will compromise clinical trials. Unfortunately, the
only way to understand if losartan will be effective in DMD boys
is clinical trials. Without evidence, we will not understand the
interaction of losartan with other compounds, and the use of the
drug will be limited to those families who are able to secure and
afford the drug. It is generally believed that treatments for DMD
will involve combination therapies, and to that extent promising
strategies must be methodically evaluated so that all children
might receive benefit.”
Additional support was provided for this research by the National
Heart Lung and Blood Institute, National Marfan Foundation, Howard
Hughes Medical Institute, Smilow Center for Marfan Syndrome Research
and the Dana and Albert “Cubby” Broccoli Center for Aortic Diseases.
The mission of the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS), a part of the Department of Health and
Human Services’ National Institutes of Health, is to support research
into the causes, treatment and prevention of arthritis and musculoskeletal
and skin diseases; the training of basic and clinical scientists
to carry out this research; and the dissemination of information
on research progress in these diseases. For more information about
NIAMS, call the information clearinghouse at (301) 495-4484 or
(877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
The mission of the National Institute of Neurological Disorders
and Stroke (NINDS) is to reduce the burden of neurological disease — a
burden borne by every age group, by every segment of society,
by people all over the world.
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
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