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Harry C. Dietz — Curing Connective Tissue Diseases

Each year, 15,000 Americans die suddenly from a ruptured aortic aneurysm – a bulge in the wall of the body's main artery leading from the heart. This bulge weakens the wall of the aorta to the point that it tears apart or bursts. It the ninth leading cause of death in men over age 55 and kills up to 2 percent of people in developed countries.

Hal Dietz has dedicated his medical career to understanding the genetic causes of these aneurysms of the aorta and how they can be prevented.

Dietz is both a pediatric geneticist and cardiologist at the Johns Hopkins University School of Medicine. He treats patients with a relatively rare inherited disorder, Marfan Syndrome, in which life-threatening aortic aneurysms are common. He is regarded as the preeminent expert on this disorder.

Dietz's earlier work in this field – following in the footsteps of a Hopkins mentor, Victor McKusick, widely hailed as the father of medical genetics – led to a new understanding of Marfan Syndrome that overturned decades of conventional wisdom. He then discovered new treatments, already in place or being tested for other conditions, for this disorder and for some apparently related diseases, including Duchenne Muscular Dystrophy.

In Marfan Syndrome, an inherited mutation causes the aortic walls to weaken. Bulges then can occur. This potentially fatal connective tissue disease is thought to have perhaps affected Abraham Lincoln, Paganini, Charles de Gaulle and the father of King Tut.

In 2005, Dietz and a fellow research scientist at Hopkins, Bart L. Loeys, identified a related connective tissue disorder that is named after them, Loeys-Dietz Syndrome. They located the two defective genes that cause this disorder, which can create weaknesses in the aortic walls of children, thus putting them at great risk at an early age.

Then Dietz found a promising therapeutic agent for these kinds of disorders – a commonly prescribed blood-pressure medication, losartan (Cozaar), which blocks a chemical that causes blood vessels to open up. In animal laboratory tests, losartan not only prevented aortic aneurysms from forming but prevented all physical manifestations of Marfan syndrome.

"It was truly a jaw-dropping moment," Dietz recalls. "It was beyond anything I could have anticipated or hoped."

Three years later, in 2008, a small study of 18 human patients yielded such encouraging results that the NIH promptly approved a large multi-center clinical trial of losartan at over 20 sites in the United States, Canada and Belgium.

Now, thanks to a $283,000 ARRA grant from the NIH, Dietz and his research team are hunting for variants in one or more genes that modify the severity of aortic aneurysms in laboratory animals with Marfan Syndrome and Loeys-Dietz Syndrome. This work could guide the way to new and even better treatments.

Dietz's research team also is using ARRA funds to compare two treatments for Loeys-Dietz Syndrome – the beta blocker medication atenenol and losartan.

"If you had asked me five years ago what I thought about the prospect of treating a connective tissue disorder with a pill," Dietz says, "I would have told you that the chances were zero."

But now he is excited about the losartan treatment because it seems to address the multi-system issues of Marfan and possibly other related connective tissue disorders.

"I think this is really going to set the stage for new treatment strategies that couldn't possibly have been thought of" using the older ways of looking at these disorders.

Dietz's research team is now a lot closer to translating their lab work into novel therapies that will prevent fatal weakening of the arteries, restore muscle growth and improve both the length and quality of life for over 30,000 Americans with these devastating genetic tissue disorders.

This article originally appeared on the Johns Hopkins University website. Reposted with permission.

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