A commonly prescribed blood pressure medication may provide the first ray of hope in preventing potentially deadly complications of Marfan syndrome, a genetic disease that weakens the structural meshwork of blood vessels.
People who have Marfan syndrome have a high risk of developing aortic aneurysm, which can lead to rupture of the heart's largest artery, causing sudden death.
In studies published in the journal Science, Howard Hughes Medical Institute researchers at Johns Hopkins University School of Medicine have shown in mice that the drug losartan, which is manufactured by Merck and sold under the brand name Cozaar, can prevent progression of Marfan syndrome and may also restore normal architecture to the wall of the aorta.
Marfan syndrome is a connective tissue disorder that affects about one in 5,000 individuals. Manifestations include long bone overgrowth, lens dislocation, emphysema, thickening and dysfunction of the heart's mitral valve, and aortic aneurysm with a predisposition for early vascular rupture and sudden death.
Losartan attenuates development of aortic aneurysm by lowering the activity of a pervasive developmental molecule called transforming growth factor beta. In a sea change in thinking about the origins of the disease, researchers have recently discovered that transforming growth factor beta - not simply a defect in a structural protein - is most likely responsible for the syndrome's catastrophic developmental defects.
"This is the first therapy for Marfan syndrome that was borne of a systematic effort to elucidate the pathogenesis of the disease," said the senior author of the study, Harry C. Dietz, a Howard Hughes Medical Institute investigator at Johns Hopkins. "I think that this is a rare example where things lived up to the promise that was expressed upon launching 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."
On the basis of data presented in the study published in Science and presentations that Dietz has made to scientists at the National Institutes of Health (NIH), the NIH is planning to launch a multicenter clinical trial to assess whether losartan might be used to prevent aortic aneurysm in children with Marfan syndrome. The clinical trial will be coordinated by the Pediatric Heart Network, which was established by the National Heart, Lung, and Blood Institute in 2001 to improve outcomes and quality of life in children who acquire or are born with heart disease. Recruitment of patients may begin by the end of summer 2006, Dietz said.
Although the clinical trials will ultimately decide the safety and efficacy of losartan treatment for patients with Marfan syndrome, Dietz said the drug's long track record as an anti-hypertensive gives him reason for optimism. "This drug has an exceptional tolerance profile. It's one of the 'go-to' drugs when people do not tolerate other anti-hypertensive medications. And it has received Food and Drug Administration approval for use in children," he said.
In 1991, Dietz and his colleagues made a significant breakthrough when they showed that mutations in the fibrillin-1 gene cause Marfan syndrome. Fibrillin-1 is a protein that is required during development to make elastic fibers in a range of tissues throughout the body.
But the cause for celebration was relatively short lived, as researchers soon realized that therapy for a systemic connective tissue disorder, such as Marfan syndrome, would be a difficult challenge indeed.
"After that discovery," Dietz recalled, "things began to look very pessimistic almost immediately. Since fibrillin-1 was a structural protein - and very important during development - there was a suggestion that people with Marfan syndrome are born without a proper quotient or quality of elastic fibers. So this really suggested that at birth, someone with Marfan syndrome already has an obligate predisposition for tissue failure later in life. To put it another way, people with Marfan never made enough of the elastic fibers that they could only make during embryogenesis."
In the early 1990s, researchers such as Dietz knew that figuring out a way to compensate for the lack of elastic fibers - particularly during early development - was a challenge that molecular medicine was not yet ready to handle. "It suggested to us that the possibility of finding a productive treatment strategy was very remote," said Dietz. "It's analogous to having a house with a rotten frame. There is no way you could imagine addressing the situation without tearing the house down and starting over."
As researchers in the Marfan's field considered their options during what Dietz calls "those dark days," some, including Dietz himself, began to call into question the structural integrity of their understanding of the syndrome. One question in particular gnawed at Dietz: How could a disease with such a complicated phenotype - overgrowth of bones, thickened mitral valves, craniofacial deformities, lung abnormalities - only be explained by structural deficiency? "It just didn't add up," he said.
In the course of their work, Dietz's lab developed a mouse model of Marfan syndrome by genetically engineering a mouse with a mutation in the fibrillin-1 gene. Genetically engineered mice are a standard way of probing the developmental function of the genes that have been altered. To help in puzzling through some of the questions that had arisen in Dietz's mind, the scientists first focused on the abnormal lung tissue in the mutant mice.
They knew that people with Marfan syndrome could develop problems that resemble destructive emphysema - which involves widening of the air spaces and can lead to rupture of the lungs. When they examined the lungs of their mice, they expected to see evidence of destruction and inflammation in the lung tissue, said Dietz. They did not think they would see emphysema-like problems in their mice early in development because the prevailing notion was that the structural changes in the tissues of Marfan syndrome patients were the cumulative result of stresses over time. In the aorta, for example, those stresses would gradually wear down the weakened vessel until a catastrophic rupture occurred. "We thought that over the course of months to years we would begin to see structural damage to the lung. Instead, we saw a diffuse widening of the air spaces in the lung right from the first day of birth without any evidence of tissue destruction or inflammation."