Hal Dietz became a scientist as well as a pediatrician to better care for young patients with Marfan syndrome. This potentially fatal connective tissue disease, which is thought to have affected Abraham Lincoln, Paganini, Charles de Gaulle, and the father of King Tut, enlarges the aorta, making it likely to tear or burst. When Dietz realized that standard treatments weren't working, he decided to find the molecular cause so better therapies could be devised. His work has led to the current clinical trial of a surprising potential treatment for Marfan syndrome: a medication used to treat high blood pressure. "If you had asked me five years ago what I thought about the prospect of treating a connective tissue disorder with a pill, I would have told you that the chances were zero," says Dietz, whose findings are also shedding light on several other diseases.
Although only 1 in 5,000 Americans has Marfan syndrome, aortic aneurysms (enlargement of the aorta) kill up to 2 percent of people in developed countries. So Dietz thought that studying Marfan syndrome would likely help many more people than just those with that disease. Moreover, Marfan syndrome involves just one faulty gene, and so is easier to study than genetically complex conditions.
Through family studies in the late 1980s, Dietz's group linked an error in the gene that encodes fibrillin-1, a connective tissue protein, to Marfan syndrome. They have since found or helped find the genes underlying four other conditions that cause aortic aneurysms, including Loeys-Dietz syndrome, named after Dietz and another Johns Hopkins scientist, Bart Loeys. Children with the syndrome, which can cause the aorta to rupture at a very early age, were previously thought to have Marfan syndrome. In 2005, however, Dietz and Loeys isolated the two genes that are defective in the disorder, and described characteristic physical features. While this work was in progress, Dietz received a photo card of a baby diagnosed with Marfan syndrome and noticed that the baby's eyes were wider apart than those of her unaffected sister. A genetic test confirmed that the baby really had Loeys-Dietz syndrome, and surgery to replace the damaged part of her aorta saved her life because it was performed much earlier than surgery for Marfan syndrome. "It was thrilling to see the concept of translational application of our work transition from an abstract concept to tangible reality," Dietz says.
After scientists link a gene to a disease, they want to know what happens when that gene is faulty. But knowing that Marfan syndrome involved a gene for a structural protein puzzled Dietz. "It became obvious that structural weakness of tissues couldn't be the whole story," he says. "For example, it couldn't explain the overgrowth of bones, abnormal facial features, valve thickening, low muscle mass, or low fat stores."
While browsing through the structures of other proteins, Dietz and others realized that fibrillin-1 looks like a protein that dampens the activity of transforming growth factor-beta (TGFβ), which has different effects on different tissues. He therefore wondered if fibrillin-1 also inhibits TGFβ. If that were the case, TGFβ would be overactive in Marfan syndrome because fibrillin-1 wouldn't keep it in check. The idea that a structural protein could regulate other proteins was a heresy in the early 1990s, because connective tissue was thought of simply as glue that holds other tissues together.
To test Dietz's idea, his group analyzed mice whose fibrillin-1 gene didn't function. These mice showed all the typical Marfan symptoms, including early death of cells that form lung tissue, overproliferation of cells in the heart's mitral valve, and muscle that can't regenerate or enlarge in response to injury or exercise. By injecting the mice with an antibody that blocks TGFβ, the researchers prevented those problems.
Fortuitously, the FDA had already approved a drug that inhibits TGFβ: losartan (Cozaar), which is used to treat high blood pressure. In mice, losartan also prevented all of the physical manifestations of Marfan syndrome the researchers had studied. "What I find very exciting is the fact that in studying aortic aneurysm we have developed a treatment not only for vascular disease but one that is truly addressing the multisystem pathogenesis of this disorder," says Dietz. The clinical trial to see if losartan can slow aortic growth better than atenolol, another blood pressure drug, began at 20 sites in the United States, Canada, and Belgium in 2007.
Dietz's progress with Marfan syndrome led him to investigate certain conditions that don't produce aortic aneurysms. For example, his group determined that losartan normalizes muscle architecture and function in a mouse model of Duchenne muscular dystrophy. They also found that people with some forms of scleroderma have altered TGFβ activity. By making mouse models of scleroderma, they want to see if losartan or a similar drug might also treat that condition.
The idea of dual-purpose structural proteins is now well accepted because other groups have made similar observations. "I think this is really going to set the stage for the development of new treatment strategies that couldn't possibly have been thought of using the old, erroneous pathogenic models," Dietz says.