Johns Hopkins’ Harry Dietz, M.D., talked about his team’s efforts to understand a gene involved in Marfan Syndrome at last week’s Discovery Lecture.
Photo by Dana Johnson
Studying the rare can help understand the common: Dietz
A captivated crowd at last week's Thomas P. Graham lecture, part of the Discovery Lecture Series, learned how a blood pressure medication may revolutionize the treatment of Marfan Syndrome, an inherited disorder that predisposes patients to blood vessel rupture and sudden death.
Harry Dietz, M.D., recounted his team's 15-year journey to understand how a single gene defect gives rise to the complicated syndrome, and how to potentially counter it with medication.
“I happen to be a physician who does research specifically to help my own patients,” said Dietz, the Victor A. McKusick Professor of Medicine and Genetics at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator.
“But there's a grander theme, and that theme is that through the study of relatively rare Mendelian disorders, there is an opportunity to gain footholds into the pathogenesis of more common forms of disease.”
Marfan Syndrome is a connective tissue disorder that affects about one in 5,000 people worldwide. It causes long-bone overgrowth (arms and legs are disproportionately long), visual disturbances, emphysema, heart valve disorders and aortic aneurysm.
During his pediatric cardiology fellowship, Dietz and colleagues discovered that mutations in the gene encoding the connective tissue protein fibrillin-1 cause Marfan Syndrome. At the time of their discovery, fibrillin-1 was known to aggregate, forming structures called microfibrils that clustered around the maturing ends of elastic fibers during embryonic development.
“This suggested that children with Marfan Syndrome are born with an inadequate number and quality of elastic fibers (because of the fibrillin-1 gene defect), and that they therefore have a structural predisposition for tissue failure later in life,” he said. “This boded very poorly for the development of treatment strategies.”
But over the next few years, Dietz and colleagues were able to refute this hypothesis. They created a mouse model of Marfan Syndome (by deleting the fibrillin-1 gene in mice) that shows many aspects of the disorder.
The striking finding in this model, Dietz said, was that just after birth there was a normal content and normal architecture of elastic fibers in the aortic vasculature, and it was only over time that the investigators observed elastic fiber fragmentation and disarray.
“This immediately suggested that there is an opportunity during postnatal life to achieve therapeutic gain,” Dietz said.
Dietz and his colleagues recognized that the fibrillin protein looked like another family of proteins that bind to the inactive growth factor TGF-beta. They reasoned that fibrillins in the context of microfibrils may be the extracellular binding partners for this inactive TGF-beta complex, and that in the absence of a sufficient quantity or quality of these microfibrils — as seen in Marfan Syndrome — there might be “promiscuous activation of TGF-beta.”
The investigators demonstrated that there was excess TGF-beta signaling in the mouse model of Marfan Syndrome. They were able to rescue structural defects in the lung, mitral valve, skeletal muscle and aortic blood vessel wall by treating the mice with antibodies that block TGF-beta signaling.
The team then looked for a drug that would mimic the effects of the TGF-beta-blocking antibodies. The drug pressure medication losartan fit the bill.
In a trial in the Marfan Syndrome mice, losartan treatment completely normalized the size and architecture of the aorta and rescued other aspects of Marfan Syndrome, including skeletal muscle regeneration and strength.
“The striking finding was that in the losartan-treated mice, no pathologist could tell them apart from wild-type (normal) mice by any parameter, Dietz said.
A pilot trial of losartan in 15 patients with severe Marfan Syndrome has demonstrated similar promising results, Dietz said, noting that he is hearing “many stories about very rapid gain of motor milestones and improvement in motor performance after treatment with losartan.”
A large multi-center clinical trial, to be conducted through the National Institutes of Health-supported Pediatric Heart Network, will compare losartan to propranolol, the current standard treatment, in patients with Marfan Syndrome. The trial will begin recruiting patients in about six weeks.
Dietz also described rescue of skeletal muscle defects in a mouse model of Duchenne muscular dystrophy treated with losartan.
The Thomas P. Graham Lecture is presented annually in honor of Thomas Graham, M.D., professor of Pediatrics, who founded and guided the Division of Pediatric Cardiology at Vanderbilt from 1971 to 2004.
For a complete schedule of the Discovery Lecture Series and archived video of previous lectures, go to www.mc.vanderbilt.edu/discoveryseries.