March 2007
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:: Archives :: Publications :: News Room :: Research :: PDF Version Research Marfan drugs, In her own words A place like home by Anne Renk Gratitudes This month's scoop |
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Marfan clinical trial begins
Clues about hemorrhagic fever
Can a blood pressure drug prevent aortic aneurysm in Marfan patients?
If results in humans are anything like they are in mice, it may be possible to prevent life-threatening heart-related complications in patients with Marfan syndrome by using an existing drug to strengthen the aorta, the main artery coming from the heart. Last month, Children's Hospital Boston enrolled its first patient in a multicenter, government-funded clinical trial to test this drug, called losartan.People with Marfan syndrome, a genetic disorder affecting about 1 in 5,000 Americans, tend to be tall with long limbs and long faces. But the disease also weakens the aorta, often causing the vessel wall to bulge out, forming an aneurysm.
Beta blockers are sometimes used to lower blood pressure and reduce stress on the aorta, but new evidence suggests that losartan may be far more protective. It inhibits signaling by transforming growth factor-beta, a protein now known to be overactive in Marfan syndrome, and blocks a cascade of cellular events that weaken aortic tissue. In a landmark 2006 study, losartan completely prevented aortic aneurysms in mice with Marfan syndrome, and even reversed existing aortic damage.
The Phase III trial, co-led by Ron Lacro, MD, director of Children's Cardiovascular Genetics clinic, aims to enroll about 600 patients aged 6 months to 25 years. They will be randomly assigned to receive losartan or the beta-blocker atenolol, and will be closely followed for three years.
"We wanted to extend the trial to young adults because people tend to get cardiovascular complications of Marfan syndrome in their late teens and early adulthood," Lacro says. "If we meet our recruitment goal, this would be the largest Marfan study ever done."
Discovery could aid control of hemorrhagic fever viruses
Researchers led by Hyeryun Choe, PhD, of Children's Pulmonary Division, have discovered the receptor through which a group of life-threatening hemorrhagic fever viruses enter the body's cells. Their findings, published online in Nature on February 7, give a clue as to the viruses' high lethality—about 30 percent of those infected die—and point the way toward sorely needed treatment strategies.The four viruses, collectively called New World arena- viruses, cause Bolivian, Venezuelan, Argentine and Brazilian hemorrhagic fevers, and are viewed as potential bioterrorism agents. Infection leads to multiple-organ damage and bleeding internally, from under the skin and from the mouth, eyes, ears and other orifices.
The receptor, identified by Jonathan Abraham, an MD-PhD student in Choe's lab, is an essential protein that enables cells to take up iron. Called transferrin receptor 1 (TfR1), it's found on virtually every cell of the body, and is especially abundant on activated immune cells—the very cells that mobilize to fight the viruses. "This may help explain why mortality is so high," says Choe.
Choe's lab will now test several antibodies that block TfR1, hoping to find one that inhibits the virus without compromising TfR1's role in iron uptake. Some of these antibodies are already clinically available, so could be tried in patients relatively soon. Choe's team also found that giving cells iron made them less susceptible to New World arenavirus infection, suggesting that iron supplements could help contain outbreaks.
Two other Children's labs have aided the work. Paul Schmidt, PhD, a fellow in the lab of Nancy Andrews, MD, PhD, who studies iron metabolism, lent expertise that helped speed up the TfR1 discovery. And back in 1999, Children's researcher and Howard Hughes Medical Institute investigator Stephen Harrison, PhD, determined TfR1's three-dimensional structure (above), knowledge that should speed the development of targeted antiviral drugs.
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