National Marfan Foundation Richmond, VA Network Group Meeting
Saturday, November 3, 2007 at 1:00pm
Cosby High School
14300 Fox Club Parkway
Midlothian, VA 23112
Guest Speaker:
Dr. Robert W. Battle, M.D.
Associate Professor of Medicine
University of Virginia School of Medicine
Department of Cardiovascular Medicine
Saving Haley's Heart - A rare genetic condition threatens the life of our little girl, but an experimental drug just might save her
From the day she was born, we marveled at our daughter’s long, thin fingers and were constantly amazed when she measured in the 96th percentile for height—especially because I’m only 5'2" and my husband Marty is 5'10". What we didn’t know was that the very characteristics we were admiring were signs of a rare and potentially fatal disorder.
Haley reached all the normal milestones in her first year: sitting at 6 months, speaking at 9, and taking her first steps soon after. But as she graduated from those first wobbly steps to keeping up with her older brother, Adam, I noticed that her feet were so flat and flexible that her ankles twisted as she walked. When she turned 2, we decided to take her to an orthopedist.
The doctor assured us that flat, flexible feet were common in toddlers. But over the next six months, Haley’s weak ankles got worse, so Marty and I decided to get a second opinion from an orthopedist in Iowa City, a two-hour drive from our home.
Searching for answers
The second orthopedist watched as Haley ran up and down the hall, measured her arms, looked inside her mouth and asked her to bend her fingers every which way. He told us that Haley was probably fine, but that she might have a connective tissue disorder and that we should have a geneticist check her out.
Before that appointment, a nurse called to ask some preliminary questions about Haley. "Has anyone in your family died suddenly from cardiac issues?" she asked. I panicked: "No! What exactly is the geneticist looking for?"
"Marfan syndrome," she replied. That was the first time I heard the words that would change all of our lives.*
A Silver Bullet for Blake - Unwilling to sit by while his youngest patients succumbed to Marfan syndrome, cardiologist Hal Dietz turned to bench science. His nearly two-decade quest in the lab has paid off big, bringing new hope to sufferers of Marfan—and a host of other devastating conditions. - by Elaine Freeman
...snip...
“It was truly a jaw-dropping moment,” Dietz told Science magazine’s reporter, throwing his usual reserve to the winds. “It was beyond anything I could have anticipated or hoped.” Now he had proof a drug already approved by the FDA might hold the answer to the “rotten frame” ravaging the bodies of Marfan patients.
...snip...
In this case, Dietz’s unique blend of inspiration and dogged persistence led to a growth factor dubbed TGF-beta as the mysterious pathway.
Transforming growth factor-beta is a family of signaling molecules that tell cells when to divide, where to migrate, what proteins to make—and when to die. Usually this occurs in an orderly, appropriate fashion. But triggered by a genetic defect, TGF-ß may give totally different directions to different cells—all resulting in inappropriate behavior.
Dietz became suspicious when he realized that the structure of a TGF-ß regulatory protein resembled fibrillin-1, the Marfan gene—and that TGF-ß regulatory proteins bind to fib-1. If a mutation in the fib-1 gene causes a fibrillin-1 deficiency, he hypothesized, it also might unleash too much TGF-ß activity, triggering a whole cascade of inappropriate behavior.
In the lungs of patients with Marfan, TGF-ß might tell cells to die inappropriately, preventing division into alveoli, the small air-filled sacs necessary for normal breathing.
In the aorta, it might tell cells to make enzymes to break down tissues.
In muscles, it might suppress the ability of stem cells to regenerate muscle. In bones, it might tell cells to divide inappropriately. Too many cells, and abnormal tissue might form—such as the overgrowth of bone in the long fingers.
Block the TGF-ß pathway and cell behavior should return to normal.
...snip...
Beyond Marfan: Losartan’s Promise - Discovering that TGF-ß is the critical pathway in Marfan could lead to breakthroughs in the treatment of other conditions. The picture that’s emerging, says Hal Dietz, “is that many forms of vascular disease,” including aortic aneurysms, “are caused by too much TGF-ß signaling.”
Dietz and his protégés are particularly excited about losartan’s potential to treat muscular dystrophy (MD). In Duchenne muscular dystrophy, the most common form, as in Marfan syndrome, muscle weakness is due to the inability of stem cells in the muscle to repair damaged muscle cells. TGF-ß turns out to be the culprit in blocking muscle cells’ normal regenerative ability. The Dietz team proved this in a mouse model, then used losartan to block the TGF-ß signal, clearly correcting the malfunction. They published their results in January 2007 in Nature Medicine.
While losartan doesn’t prevent muscle destruction, it facilitates regeneration of new muscle cells. For MD patients, this could slow progression of the disease and improve muscle performance and breathing—without pernicious steroids. To test this possibility, Ronald Cohn—who now has funding to establish his own lab—is planning a clinical trial with the Muscular Dystrophy Association.
Dietz’s collaborators also are pursuing other leads for losartan. One postdoc is looking at a geriatric population: What’s the difference in body mass of individuals who took losartan for hypertension vs. those prescribed a beta blocker? Another is looking at rare genetic models of premature aging. Still another is focusing on muscle weakness in patients on chemotherapy. Losartan might have a role there, too. Elaine Freeman*
What an exciting article about Hal Dietz's research on TGF-ß and Losartan! Thanks to Dr. Loren Cobb for sharing this article with me.
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.*
National Marfan Foundation - Clinical Trial Update Info
All clinical trial sites will now take calls or email inquiries from people interested in the clinical trial. All sites will take names and get back to you when they are ready to begin enrollment. Some sites have already begun enrollment. To view the list of trial sites, please click here and select the "List of Clinical Trial Enrollment Sites" link.
Choose the site of interest to you and contact the coordinator. The trial staff will answer your questions about the trial and decide if you are eligible. If you have questions about this message you can contact:
Karen Wolk, LMSW
Director of Support and Volunteer Development
National Marfan Foundation
22 Manhasset Avenue
Port Washington, NY 11050
1-800-862-7326 ext. 22*
with questions or comments about this web site.
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