Into the Clinic

In the early 1990s, with the help of Duke surgical fellow Carmelo Milano, postdoctoral fellow Walter Koch and a team of other trainees, Lefkowitz began to examine the possibility of using the bAR system as a kind of molecular ventricular-assist device—a way to help a failing heart increase its ability to pump. Their idea has its origins in Lefkowitz's early work and in basic knowledge of how the heart responds to stress.

Lefkowitz knew that when the heart is under stress, it increases the production and release of the stress hormone norepinephrine, which binds to bARs located on heart cells. This stimulation initially helps the heart beat faster and more powerfully, but it quickly becomes self-defeating: The norepinephrine-stimulated receptors become desensitized by a second molecule called b-adrenergic receptor kinase (bARK).

The group demonstrated in 1994 that mice genetically altered to produce excess b₂ARs have supercharged hearts that beat faster and stronger than normal mice. They reported in the April 24, 1994, issue of Science that these mice mimicked normal animals treated with the human heart failure drug dobutamine—even though the mice didn't receive any drugs.

This finding was quickly followed in 1995 with a report on genetically altered mice that produce too much bARK in their hearts. These mice mimic aspects of congestive heart failure in humans. When the researchers injected a synthetic adrenaline-like hormone, the mice couldn't contract their heart muscles as well or increase their heart rate as much as normal mice. The transgenic mice displayed a lack of hormone response similar to that seen in patients with heart failure. The study confirmed what in vitro studies suggested: Too much bARK desensitizes the bAR system so that the heart can no longer recognize hormone stimulation.

Once they were convinced that increased levels of bARK reduce the ability of the heart to respond to hormones, the researchers wondered whether they could restore heart function by blocking bARK. As it happened, Koch had been offered a position in the surgery department at Duke and saw it as an ideal opportunity to take Lefkowitz's work into the clinic, with the goal of delivering genes, or perhaps small molecules, to treat or even prevent heart failure.

Koch designed a molecule that competes with the normal bARK in heart cells, thereby diluting its effect. First in transgenic mice and now in rabbit models, Koch, Lefkowitz and their surgical colleagues have shown that the bARK inhibitor keeps heart cells sensitive to hormone stimulation when normal heart cells would have become desensitized.

Their work has caught the interest of several pharmaceutical companies that are now testing their own bARK inhibitors. Although neither Koch nor Lefkowitz will speculate on when clinical trials might begin, it is clear the clinical progress pleases Lefkowitz.

"My father died in 1963, right on the cusp [of research progress]," he says. "The first coronary artery surgery was performed in this country in the mid-1960s. My father never had a cath [coronary artery catheterization], he never had anything. If he were here, I believe he would be pleased," Lefkowitz says.

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