New approach promises greater success for predicting drug safety
| Date: May 4, 2009 | 
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Bar Harbor, Maine – Adverse reactions to medications represent one of the leading causes of death in the United States. But there may be a way to predict who is most likely to suffer a toxic side effect to a drug before it's prescribed.
In a study published online May 4 in the journal Genome Research, scientists at The Jackson Laboratory in Bar Harbor, Maine, the University of North Carolina at Chapel Hill, and other institutions report a new approach to testing drugs for potential toxicity, one that could someday result in more people benefiting from existing drugs.
In effect, the study has created a system that enables researchers to gather interesting clues about what makes some people susceptible to drug toxicity and then explore them in mouse models. But the team believes perhaps the greatest impact this research could have is to improve the drug development process – to begin to understand what properties of a drug can make it toxic, and to identify the people most vulnerable to those toxicities.
A large part of the cost of developing a new drug that can go out for therapeutic use lies in the clinical trials, says Jackson Laboratory Senior Research Fellow Ken Paigen, Ph.D., a coauthor of the study, "because the vast majority of the drugs that enter clinical trials don't make it through. They either turn out to lack efficacy or they have side effects that are too serious to put the drug into the general population."
See Dr. Paigen explain these findings in an informal, 6-minute video
Paul Watkins, M.D., distinguished professor of medicine at UNC and study co-author, adds that over the last several years, the pharmaceutical industry has made progress in developing drugs that are likely to work, but sometimes potentially deadly effects still do not emerge until they are on the market. In the case of Vioxx, millions of people had already used the pain-killer and arthritis medication before researchers found it could increase the risk of having a heart attack or stroke.
"The reality is that there is no safe drug," Watkins said. "Good drugs are bad for some people. Because different people respond differently to drugs, where you draw the line is not exactly black and white."
But Watkins also argues that while drugs currently on the market are not entirely safe, they are harmless in 99.9 percent of people. Therefore, if it were possible to identify in advance the one person in 1,000 that will react poorly, scientists could make drugs that are safe for everybody.
Paigen says that his colleagues at The Jackson Laboratory had already established, through experiments using a variety of mouse strains, that "we could mimic the genetic diversity of human populations, and that we could use the vast quantity of genetic information we have about the mouse to make a good guess as to what genes might be involved in drug responses.”
At the level of gene differences, mice and humans are strikingly similar. More often than not, if a researcher finds a gene variant that makes a mouse more susceptible to disease they will also be able to find a counterpart in humans that has the same effect. The study's senior author, David Threadgill, Ph.D., professor of genetics in the University of North Carolina at Chapel Hill School of Medicine, and his colleagues took a group of JAX® Mice from The Jackson Laboratory that were genetically distinct from each other and looked to see if variations in their genetic makeup could predict their response to treatment with acetaminophen (the chemical component of Tylenol and extensively used in liver toxicity studies).
Mice are two to four times more genetically variable than humans, said Threadgill. “If you can exploit this variation in a laboratory setting, you can treat it almost like a population of people.”
After identifying many genes that were associated with side effects to acetaminophen in their mouse models, Threadgill and his colleagues then went back to humans to see which of these gene variants were also associated with response to the drug.
The researchers found that a subset of people taking the maximum daily recommended dose of the drug exhibited an elevation in specific enzymes that can indicate damage to the liver, Threadgill says. Variations in one gene in particular – called CD44 – were responsible for almost half of the differences in toxic side effects experienced from one person to another.
"One of the fascinating things that came out of this study was that the genetic variation in acetaminophen toxicity is not what all of the toxicologists would have predicted in the first place," says Paigen. "CD44 doesn’t have anything to do with the rate of metabolism of the drug, but it does have something to do with the immune response."
"Just look at the drug industry’s own numbers on how much it costs to develop a drug," says Threadgill. "To get a drug to the market takes close to $1 billion, whereas a study like this can be done for $100,000. This approach could be used to determine early on if the drug is not going to be viable because of a high level of toxicity, or it could give important insights into whether the drug is likely to be beneficial."
Jackson Research Scientist Molly Bogue, Ph.D., is another coauthor of the paper. The following laboratories also contributed to the study: the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.; Verto Institute Research Laboratories and Cancer Institute of New Jersey, both in New Brunswick, N.J.; Novartis Institute in San Diego, Calif.; Purdue Pharma L.P. in Stamford, Conn.; and the department of genetics at North Carolina State University in Raleigh.
The research was funded by the National Institutes of Health.
The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif. Its mission is to discover the genetic basis for preventing, treating and curing human diseases, and to enable research and education for the global biomedical community. The Laboratory is the world's source for more than 4,000 strains of genetically defined mice, is home of the mouse genome database and is an international hub for scientific courses, conferences, training and education.
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Harrill, A.H., Watkins, P.B., Su, S., Ross, P.K., Harbourt, D.E., Stylianou, I.M., Boorman, G.A., Russo, M.W., Sackler, R.S., Harris, S.C., Contractor, T., Wiltshire, T., Rusyn, I., and Threadgill, D.W. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res. doi:10.1101/gr.090241.108. Published online ahead of print on May 5, 2009.
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