That observation led to a radical change in Dietz's thinking. He began to suspect that many features of Marfan syndrome—for example, the fragile aorta that eventually ruptures—might not be caused by a simple weakness of the tissues imposed by deficiency of a structural protein. Instead, he started looking for abnormal patterns in a developmental program. In research spanning several years, Dietz and his colleagues proved time and again—in studies of the lungs, aorta, and mitral valve—that the culprit was excessive levels of a critical developmental signaling molecule called transforming growth factor beta (TGF-beta) that is normally regulated by fibrillin-1.

The next step was to see if they could prevent features of Marfan syndrome by blocking such signaling abnormalities, which led them to losartan, a blood pressure medication that other researchers had found to be active against TGF-beta in studies of chronic renal disease.

Dietz and his colleagues at Hopkins set up a study in mice to compare losartan, propranolol (a blood pressure agent that is used prophylactically in Marfan patients to prevent tears in the aorta), and a placebo. The studies, published in the April 7, 2006, issue of Science, revealed that the mice that received losartan showed no progression of aneurysm formation and even an apparent reversal of aortic pathology. “Those mice had normal aortic root growth, normal aortic root size, and normal aortic wall thickness and architecture,” says Dietz. “Essentially, losartan-treated Marfan mice could not be distinguished from normal mice.” Losartan improved other manifestations of Marfan syndrome in the mice, as well, including abnormal lung development.

Dietz is optimistic that additional research will show that losartan might actually remodel the abnormal architecture of the aortic wall. It is also possible, he adds, that lessons learned from these studies could be applied to other causes of aortic aneurysm. Dietz and his collaborators have recently shown that two other aortic aneurysm syndromes, Loeys-Dietz syndrome and arterial tortuosity syndrome, are also caused by altered TGF-beta signaling. “Aortic aneurysm is a major public health burden,” says Dietz. “About one to two percent of the population in industrialized countries dies from it. We are now targeting the more common forms of aneurysm for study.”

		Encouraged by Dietz's work, the National Institutes of Health (NIH) is launching a multicenter clinical trial to assess whether losartan might be used to prevent aortic aneurysm in children with Marfan syndrome. The trial will be coordinated by the Pediatric Heart Network, established in 2001, to improve outcomes and quality of life in children with heart disease. Recruitment of patients may begin by the end of summer 2006. “This is the first therapy for Marfan syndrome that was born of a systematic effort to elucidate the pathogenesis of the disease,” says Dietz. “It is a rare example of things living up to the promise expressed at the launch of the Human Genome Project: If we can identify the genes responsible for a disease, then we will uncover unanticipated mechanisms behind the disease and be in a better position to design rational therapeutic strategies.” Information about the clinical trial is available from the National Marfan Foundation at www.marfan.org or (800) 8-MARFAN.

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