Marfan Syndrome

[Guest guest]

This was sent to me from another group. I thought it may interest some of you

as well.

Connie

Re: [muscledisease] News

Thank you for sharing this!

bill andrews <billgepump@...> wrote: Common blood pressure drug treats

muscular dystrophy in mice Clinical promise grows out of new twists on Marfan

syndrome research Researchers at s Hopkins have shown that a drug commonly

used to lower blood pressure reverses muscle wasting in genetically engineered

mice with Marfan syndrome and also prevents muscle degeneration in mice with

Duchenne muscular dystrophy. The results are reported online this week at Nature

Medicine.

In 2006, a team led by Harry " Hal " Dietz, M.D., discovered that treating Marfan

mice with losartan (Cozaar) dramatically strengthens the aorta, the major artery

carrying blood away from the heart, and prevents enlargement and risk of

bursting, a condition known as aortic aneurysm. A clinical trial to assess how

effective losartan is for treating people with Marfan will launch within weeks.

" In addition to the aortic defect, children with severe Marfan syndrome often

have very small, weak muscles, and adults with Marfan often can't gain muscle

mass despite adequate nutrition and exercise, " explains Dietz, a professor at

the McKusick-s Institute of Genetic Medicine at The s Hopkins

University School of Medicine.

Dietz and his colleagues had previously discovered that many features of Marfan

syndrome, including aortic aneurysm, arise from excess activity of TGF-beta, a

protein that instructs cell behavior. Marfan mice have muscles containing much

scar tissue between unusually small muscle fibers, which also show evidence of

too much TGF-beta activity. Dietz's team reasoned that blocking the activity of

TGF-beta might restore normal muscle structure and function.

First, the research team injected Marfan mice with a protein that binds TGF-beta

and renders it inactive. This TGF-beta-blocking protein caused muscle fibers in

these mice to grow bigger than those in untreated Marfan mice. " Not only did the

muscles look bigger and better under the microscope, " says Dietz, " the mice were

also stronger and showed reduced fatigue. "

The team then treated Marfan mice with losartan, a medication known to be safe

in treating hypertension in all age groups and more importantly, known to block

TGF-beta activity. Losartan treatment over six months " completely restored

muscle architecture " and vastly improved strength, according to Dietz.

Further study pinpointed how too much TGF-beta activity leads to this weakened

muscle architecture. According to Cohn, M.D., lead author on this study,

normal muscle, by mobilizing muscle stem cells, can repair itself after injury.

The team discovered that excessive TGF-beta blocks muscle regeneration and

repair. " The simplest things can injure muscle, " explains Cohn, an assistant

professor of pediatrics and neurology at Hopkins. " Running a mile down the

street causes microscopic tears in leg muscles, which normally go unnoticed

because muscles are so efficient at repairing themselves. "

Dietz's team then wondered whether the muscle improvement from blocking TGF-beta

was specific to Marfan syndrome or possibly represented a strategy that could be

applied to other muscle diseases such as Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy, the most common form of incurable muscular

dystrophy in children, generally leads to death in early adulthood or before.

DMD causes muscle fibers to be incredibly fragile. As a person with DMD ages,

their muscles slowly lose the ability to regenerate and repair, which leads to

loss of muscle function, explains Cohn.

TGF-beta never had been implicated as a cause of the inability to repair muscle

in DMD. So the researchers examined muscles from mice genetically engineered to

have DMD and found evidence of increased TGF-beta activity.

The team treated one group of DMD mice with TGF-beta-blocking protein and

another group with losartan. Both groups of treated mice showed completely

restored ability to regenerate muscle after injury, whereas untreated mice had

large patches of scar tissue in place of muscle. Losartan treatment over many

months preserved muscle architecture " over the long haul, " says Dietz.

The team then measured muscle strength of untreated DMD mice as well as mice

treated for nine months with losartan by connecting the muscles to tiny

" force-meters " that measured contraction after an electrical stimulus. While the

untreated DMD muscles were " very weak, " according to Dietz, losartan-treated DMD

muscles were " indistinguishable " from normal muscles in how strongly they

contracted.

" We may have a real treatment alternative for a fatal disease-Duchenne muscular

dystrophy-that improves both length and quality of life, " says Cohn.

" For so many reasons, we're excited about these studies and their potential to

transform the care of patients with both Marfan syndrome and Duchenne muscular

dystrophy, " says Dietz. " First, this treatment strategy comes from understanding

the basic science, the molecular underpinnings of the disease. Second, the

treatment has worked exceptionally well in animal models. Third, we are not

dealing with a mysterious compound that was simply pulled off the shelf -

losartan has already been proven safe, " says Dietz.

" Furthermore, losing the ability to regenerate muscle over time is seen in many

inherited and acquired muscle diseases and is even part of the normal aging

process, " adds Cohn. " We may only be seeing the tip of the iceberg. "

Losartan, first approved for use as a blood pressure medication in 1995 by the

U.S. Food and Drug Administration, often is used as an alternative to other

antihypertensive drugs in people who cannot tolerate other blood pressure

medicines.

###

s Hopkins Medicine

Media Relations and Public Affairs

Media Contact:

Margaret Putney; mputney1@...

Jan. 19, 2007

************************************************************ EMBARGOED FOR

RELEASE UNTIL SUNDAY, JAN. 21 AT 1 P.M.

E.T.*************************************************************

The research was funded by the Medical Institute, the National

Institutes of Health, the Smilow Center for Marfan Syndrome Research, the Dana

and Albert " Cubby " Broccoli Center for Aortic Diseases and the National Marfan

Foundation.

Authors on the paper are Cohn, Christel van Erp, Habashi, Arshia

Soleimani, Klein, Lisi, Gamradt, Colette ap Rhys, Tammy

Holm, Bart Loeys, Judge, and Dietz, all of Hopkins; Ward of

the University of land; and Francesco of the University of Medicine

and Dentistry of New Jersey- Wood Medical School.

On the Web:

http://www.hopkinsmedicine.org/geneticmedicine/index.html

http://www.nature.com/nm/

http://www.hopkinsmedicine.org/Press_releases/2006/04_06_06.html

http://www.marfan.org

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