Heading Off Heart Attacks

A potential genetic test for cardiovascular risk shows how “pharmacogenomics” is coming into its own.

Of course children don’t worry much about heart attacks. But what if there were a test that could predict how vulnerable a child was to cardiovascular disease later in life? Then doctors might be able to counsel their patients about making lifestyle changes, or give a child preventative medicines before their arteries started clogging up.

That’s the dream of pharmacogenomics – the practice of tailoring treatments to any individual’s unique genetic make-up. Since the completion in 2003 of the human genome – an entire readout of the sequence of nucleotides in human DNA – this emerging field of medicine has been dogged by skepticism and unmet promises. But as pharmacogenomics tests and treatments are starting to materialize and technological advances in the laboratory are speeding development even further, once-doubtful drug companies are beginning to get on board.

“The level of interest has definitely heightened. People are no longer asking, ‘is this for real?’” says Lawrence Lesko, director of the office of clinical pharmacology and biopharmaceutics at the U.S. Food and Drug Administration in Rockville, MD. “This year there is more of a discussion of how long it will take, rather than will it work.”

Thomas J. White, vice president of research at Celera Diagnostics in Alameda, CA, is one of the researchers trying to turn pharmacogenomics into more than an exotic tongue-twister. His team has extracted data from thousands of patients and assembled a selection of tiny genetic variations – usually in the form of flipped nucleotides, also known as a single nucleotide polymorphisms, or SNPs – that influence a person’s risk of heart disease. Researchers can then convert these variations into a cardiovascular risk score, which could one day be used as a diagnostic test.

According to Celera’s findings, presented at a Scientific American’s Targeted Medicine 2005 meeting in New York last week, people who carry two or more of these variations have a 70 percent greater chance of having cardiac trouble than those with fewer of the variations.

“It’s still early, but this could take the place of family history,” says White. “If your father has heart disease, you don’t know what that means for your own risk, because only half your genes came from him.” White is now analyzing the results from clinical trials of the popular cholesterol-lowering drugs known as statins, to see if the same risk factors can predict who will respond best to the drugs.

Some of the genetic variations that influence diseases and patients’ responses to treatments are simple. Last year, for example, scientists discovered small genetic changes in a key enzyme that make the cancer drugs Iressa and Tarceva much more effective in people who carry the mutation. And, in January 2005, the FDA approved a diagnostic test, produced by Swiss drug-maker Roche, that predicts how people with different variations in the DNA that codes for two enzymes will metabolize many popular drugs.

But the ultimate goal of pharmacogenomics is to find tests and treatments based on a snapshot of a person’s entire genetic makeup. “We want to go from looking at a few genes to looking at all the genes and SNPs in a cell,” says Nicholas Dracopoli, vice president of clinical discovery at Bristol-Myers Squibb in Princeton, NJ.

Cancer is one of the diseases that researchers believe will eventually yield to pharmacogenomics. Since most cancers are the result of multiple genetic missteps, scientists want to create multi-faceted therapies, similar to the anti-viral cocktails used against HIV. “If we can hit the tumor with combo therapy, it will be far more effective than managing the disease one stage at a time,” says Dracopoli.

Cheaper and faster DNA sequencing and the availability of the HapMap – a detailed map of small genetic variations in humans, a first draft of which was completed in October – will be crucial for identifying drug targets or disease markers. “With the HapMap, we now have a tool to interrogate genetic changes relatively inexpensively across the entire genome,” Dracopoli says.

Another key to speeding the transition to pharmacogenomics, says Dracopoli, will be to look for genetic markers that predict response to a drug at the same time that the drug is being developed. The FDA recommended such an approach in a set of guidelines for pharmacogenomics released in March. For most of the currently available targeted drugs, the specific mutation that makes a person respond well to a drug was identified in academic labs after the drug had been approved. But earlier integration is the key to bringing diagnostic tests and targeted therapies to the clinic faster, says Dracopoli.

According to Brian Spear, director for genomic and proteomic technologies at Abbott Laboratories in North Chicago, IL, many companies already collect genetic information in early clinical trials, in order to analyze differences in the way a drug is metabolized.

But incorporating testing into later stages of clinical testing will prove more difficult, he says. Scientists would first need to identify the group of people in a trial who respond well to a drug, then figure out which genetic variations were linked to that response. They would then need to confirm those markers in additional clinical trials, which drug companies fear could be a lengthy and expensive process.

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