Taking the blinders off  pg. 3

When an MMP inhibitor is given to block the enzyme, the beacon doesn’t flash as brightly. In this way, the researchers hope to determine the dose of drug necessary to inhibit these enzymes, as well as which patients are most likely to respond to therapy.

“What we found was a genetic polymorphism which is much more common in African-Americans than in Caucasians … This was a completely unexpected finding … When you propose these genetic studies, people will say, ‘Well, you’re going on a fishing expedition.’ And I say, ‘Yeah, but this time we caught a whale.’” David W. Haas, M.D., principal investigator, AIDS Clinical Trials Unit at Vanderbilt
Photo by Anne Rayner
“We’re talking about cellular-based screening, high-content screening,” says David W. Piston, Ph.D., professor of Molecular Physiology and Biophysics who is participating in the research. “If you’re doing front-line screening in the cell, you’re two steps closer to the patient.”

Eventually, data from these studies will be integrated with data from genomic and proteomic studies to build “3-D models” that more accurately predict drug activity. “You’re going to find a lot fewer things that take you down the wrong path,” Piston predicts.

Sidelining the side effects

One of the biggest barriers to the successful launch of a drug is the adverse drug effect or unexpected side effect that may not become apparent until late in clinical testing or after marketing.

While the adverse effect may occur in only a tiny minority of patients, it may be serious enough that the drug company has no choice but to flush the entire effort—perhaps 12 years of work and up to a billion-dollar investment—down the drain.

Advances in genetic research may come to the rescue. In the late 1970s and early 1980s, Vanderbilt scientists led by the late Grant Wilkinson, Ph.D., D.Sc., identified some of the first polymorphisms, or genetic variations, in a group of liver enzymes called cytochrome P450s that metabolize or break down drugs in the body. Drugs are more likely to reach toxic levels in people whose enzymes do a poor job breaking them down.

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