February 16, 2001

Tailor-made prescriptions focus of cardiovascular research grant

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Dr. Dan M. Roden will use a $500,000 grant to study pharmacogenomics. (photo by Dana Johnson)

Tailor-made prescriptions focus of cardiovascular research grant

Dr. Dan M. Roden, William Stokes Professor of Experimental Therapeutics, Medicine, and Pharmacology, has been awarded a Bristol-Myers Squibb Unrestricted Cardiovascular Research Grant. The five-year, $500,000 grant comes with no-strings-attached. Roden can apply the research funds to whatever projects he chooses.

“A grant out of the blue like this is an interesting form of recognition,” said Roden, who is also director of the division of Clinical Pharmacology. He will use the award to study the genetic variability that affects how individual patients respond to drugs.

This burgeoning research area, called “pharmacogenomics,” is expected to lead to an age of tailor-made prescriptions – medicines carefully matched to patients’ personal genetic codes, Roden said.

It has long been recognized that individuals respond differently to drugs. Given the same drug, some patients have a better-than-expected response, while others experience uncomfortable or even life-threatening side effects.

“It makes sense that the variability in drug responses that we have always observed relates to variability in the genome, specifically in proteins that control individual responses to drugs,” Roden said.

Variation in the genome most often takes the form of single-letter changes littered among the three billion letters that spell out the human genetic code. Scientists believe that these “single nucleotide polymorphisms,” or SNPs (pronounced “snips”), will reveal who will benefit from a certain drug, who will not, and who will suffer serious side effects. Collections of SNPs also will likely serve as predictors of disease risk.

Roden is interested in responses to medications that impact the electrical activity of the heart, particularly the “repolarization process” that returns cardiac cells to their resting state after a burst of electrical activity.

Theoretically, drugs that prolong cardiac repolarization should prevent arrhythmias, Roden said. But paradoxically, such drugs often “trigger arrhythmias, rather than suppress them,” he said.

In fact, the problem of triggering arrhythmias is not unique to antiarrhythmic drugs. A number of common and widely used antibiotic, antihistamine, and antipsychotic medications also have the same devastating side effect in some individuals.

“A number of drugs have been restricted or even pulled from the market because they can cause a peculiar and potentially fatal arrhythmia related to repolarization,” Roden said. “This problem is one that is having a major impact on the drug development process.”

One of Roden’s goals is to understand the molecules involved and the genetic variations that predispose an individual to suffering a life-threatening arrhythmia.

“Cardiac repolarization is a nice model system for pharmacogenomic studies because we understand many of the molecular players that perform a highly choreographed ballet to produce cardiac electrical activity,” Roden said. “A drug may target one participant of that ballet, but it is the genomic variability in the whole system that modulates the response to that drug.”

The proteins that dance in the electrical activity ballet are all “candidates” for variations that could lead to arrhythmias. Roden and collaborator Dr. Alfred L. George Jr., Grant W. Liddle Professor of Medicine and director of the division of Genetic Medicine, have been collecting DNA samples from patients who experience unusual arrhythmias following drug therapy for nearly 10 years. They are now systematically searching for SNPs (the single letter changes) in candidate genes that participate in controlling cardiac electrical activity.

“At the time we started collecting DNA, we didn’t know what candidate genes we would be examining, but we knew that we would eventually find them,” Roden said. “So we’re a little ahead of the game.”

The hope is that future patients will be screened for SNPs that predict unusual drug therapy-induced arrhythmias, and if appropriate, excluded from taking drugs with this side effect. Roden believes similar genomic approaches to predict responses to many different drugs will be developed, although validation of the concepts is still needed, he said.

Pharmacogenomic studies require large groups of patients with well-characterized drug responses – not only adverse effects like the arrhythmias that intrigue Roden, but also unusually good responses.

“Pharmacogenomic research requires a coordinated effort on the part of many different groups: clinical investigators to characterize individual responses to drugs, the genetic infrastructure to collect and archive DNA, laboratory geneticists, epidemiologists, and physiologists to identify candidate genes and to search for changes,” Roden said. “Above all, it requires an institutional commitment to this type of effort. Vanderbilt has made that commitment in numerous ways – it has supported the electronic medical record system (MARS), planned for DNA sample acquisition and storage, and substantially invested in genetics research in many departments.”

“I believe that pharmacogenomics is the future of clinical pharmacology, and indeed of all therapeutics,” Roden said.

Roden is one of two new recipients of the Bristol-Myers Squibb Unrestricted Cardiovascular Research Grant. Bristol-Myers Squibb initiated its unrestricted grants program in 1977. Since then, the company has committed more than $87 million to funding cancer, nutrition, orthopaedic, neuroscience, cardiovascular, infectious diseases, and metabolic diseases research.