FT. LAUDERDALE, Fla. _ Kicking off the opening session Sundaymorning of this year's biotechnology symposium, biochemist RobertLefkowitz accepted the annual Lynen Lecture award by speaking on"G-Protein-coupled receptors and receptor kinases: From molecularbiology to potential therapeutic applications."

Lefkowitz, a Howard Hughes Medical Research Institute investigatorsince 1976, holds an endowed professorship at Duke UniversitySchool of Medicine.

He addressed some 500 academic and industrial scientists attendingthe symposium originated in 1968 by the University of Miami'sbiochemistry department.

This year's symposium theme is "Advances in Gene Technology:Therapeutic Strategies in Molecular Medicine."

After detailing for his audience the molecular and genetic workingsof the G-protein adrenergic receptor system, from its key connectionwith the neurosensory mechanisms of sight and smell to its potentialfor treating heart failure, Lefkowitz updated this last aspect to thepoint of gene therapy, in an interview with BioWorld Today.

"At least 10 years ago we discovered an enzyme, which we call thebeta-adrenergic receptor kinase [b-ARK]," he said. "This enzyme isfound in the heart as well as in many other tissues. In concert withseveral other proteins, b-ARK serves to shut down adrenergic beta-adrenergic receptor function _ destabilize the receptors."

He continued: "It appears that this b-ARK system is desensitizing thereceptors in heart failure, so if one could overcome thatdesensitization, one could have more powerful contractions of theheart, and this might be a strategy to try to develop as an approach toheart failure."

Currently used drugs, such as propranolol, he observed, are usefulbecause "by blocking the adrenergic system, it can make theheartbeat less strong, less powerful and less rapid. That's useful inconditions such as certain arrhythmias of the heart, in hypertensionand in angina.

"But sometimes," Lefkowitz added, "we need things to work a littlemore powerfully, as when the heart fails. Congestive heart failure is avery important medical condition, which affects four or five millionpeople in the U.S., and is a leading cause of mortality. In heartfailure, the number of receptors declines, and even those that remaindon't function normally. Their function is depressed.

"It appears that somehow the system becomes desensitized toadrenaline action, in response to the fact that in heart failure the bodyis already driving the heart too much with adrenaline," he said.

Enter The Beta-Adrenergic Receptor Kinase Enzyme

As a first step in testing that idea, Lefkowitz and his lab madetransgenic mice, which express an artificial gene that encodes aprotein inhibitor of b-ARK. In vitro, the team had shown that thisprotein reduces the enzymatic activity of b-ARK, and hence its abilityto shut down beta receptor function. A promoter regulating that geneensured that its protein "would be expressed only in the heart, and atvery high levels _ a fact we observed."

This provided for a test of his hypothesis. "The question is,"Lefkowitz observed, "Does down-inhibiting b-ARK, an enzymewhich tends to oppose beta-receptor function, alter cardiaccontractility in essentially otherwise normal mice? The answer turnsout to be yes; there's a pronounced increase in cardiac contracility inthese transgenic animals. Their hearts beat much more strongly withthe b-ARK enzyme inhibited."

This gene, expressed in the hearts of normal, wild-type (non-transgenic) animals, increased their cardiac contractility as well,Lefkowitz said, "as I strongly presumed it would."

"The next step," he went on, "would be to put such animals into heartfailure with one or another technique, and see if this treatmentrescues them from heart failure. If it does, that will be the proof-of-concept, and one would be then in a position to think about clinicalwork."

He said he's already thinking about it, but rabbits come first. "Wehave constructed a recombinant adenovirus, which is currently thevehicle of choice for doing gene transfer experiments, and we havesucceeded in injecting this vector by catheterization down thecoronary arteries of live rabbits. By using marker genes, such as beta-galactosidase or luciferase, we know we can achieve good expressionof these transgenes in cardiac tissue.

"So we are now ready," Lefkowitz said, "to start injecting these b-ARK inhibitors, to see what that does to cardiac function."

He and Duke have patent protection pending on their approach, andno tie-in yet with a commercial company. "But we are actually in theprocess of negotiating with Genzyme for a license on some of theseideas," Lefkowitz said. n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.