What began as a hunch may turn into a blessing for hundreds of thousands of people. Two years ago, doctors suspected that an old blood pressure drug might help people with Marfan syndrome, which can cause deadly ruptures of the aorta; and today, they report success in a small group of children. The work is preliminary, though, and did not include a control group, so it's hard to say what effect the drug will have on most people with the disease.
Marfan syndrome is a relatively rare genetic condition in which the body's connective tissue is defective, but its most dangerous manifestation is in the aorta. Over time, the large artery that exits the heart stretches and grows weaker, until, if not surgically replaced, it risks rupturing. Studying a mouse model of Marfan, pediatric cardiologist Harry Dietz of Johns Hopkins University in Baltimore, Maryland, found that the animals shared a defect that hadn't been previously considered: an overactive protein called transforming growth factor-β (TGF-β). In 2006, Dietz reported in Science that giving these mice an old blood pressure drug, losartan, which blocks TGF-β, prevented aneurysms.
Physicians immediately began recruiting hundreds of people for a clinical trial of the drug, and that study is ongoing. In addition, Dietz says his team felt compelled to try losartan in a much smaller group of children and teenagers with Marfan whose aortas were rapidly deteriorating and who weren't being helped by standard treatment. That group of 18 ranged in age from 14 months to 16 years old. Seventeen of them received losartan, and the 18th got a closely related blood pressure drug, irbesartan; they were on the medication for 1 to 3 years. The drug seemed to help the children as it had the mice: Before the therapy, the children's aortas had been expanding dangerously by about 3.5 millimeters each year. Once they began receiving either drug, that pace screeched to 0.46 millimeters a year, the group reports in the New England Journal of Medicine. "It's highly suggestive" that losartan was behind this benefit, says Dietz.
This new finding "is about as good as it gets," says Kenneth Chien, who directs the Massachusetts General Hospital cardiovascular research center in Boston. "They've got the mechanism, they've got the results in mice, [and] they've got the suggestion" that losartan works in advanced disease.
Still, Dietz emphasizes that the story is far from over. The finding is very preliminary and needs to be repeated with controls in the large clinical trial that's ongoing, agrees Peter Byers, a medical geneticist at the University of Washington, Seattle. But there is a new hurdle: now that people affected by Marfan are aware that a potentially effective drug is out there, says Chien, "you have to convince people to enter a study knowing that they have [only] a 50% chance of getting the drug." Nevertheless, Dietz says the clinical trial is on track and about halfway toward its recruitment goal.