New Mouse Panel Approach May Improve Drug Safety
JAX® NOTES Issue 514, Summer 2009
Each day, millions of people worldwide battle disease — putting their trust in drugs developed to treat their conditions. Unfortunately, these drugs do not always live up to expectations, or have unforeseen health effects on some individuals that necessitate their removal from the market. This can cost pharmaceutical companies billions of dollars and erode both consumer and investor confidence as exemplified by the Vioxx recall.
JAX Professor Kenneth Paigen, Ph.D.
Liver damage is a common reason for the removal of many experimental drugs from clinical trials and why some approved drugs are later taken off the market (Kiberstis 2009). More than a third of all cases of acute liver failure in the United States have been attributed to acetaminophen overdose (Lee 2003).
The Food and Drug Administration has responded by requiring manufacturers of many acetaminophen-based drugs such as Tylenol to add black box label warnings or remove their products from the shelf entirely. This raises the question as to why some drugs make it successfully through clinical trials, only to be subsequently pulled from the market.
The answer lies with genetic variability which plays a significant role in human differential susceptibility to drug toxicity. In the past, human association studies were used to evaluate this issue. But such studies are labor-intensive, costly and often slow to generate results. Today a new approach is available to better model this variability in pre-clinical trials using panels of mice.
Watch a video of Professor Paigen explaining the research on acetaminophen‑induced liver damage.
The development of this new approach began when a collaborative research group headed by Dr. David Threadgill of the University of North Carolina, JAX scientists Professor Ken Paigen, Dr. Molly Bogue, and former postdoctoral fellow Ioannis Stylianou, decided to look for the genetic variants responsible for acetaminophen‑induced liver injury in mice. Using a panel of 36 JAX® Mice strains from the Mouse Phenome Project (MPP) the researchers discovered variations in four genes that modulate acetaminophen-induced liver injury in mice. When they searched for variants of these four genes in humans they found that CD44, the human ortholog of one of the mouse genes, modulates acetaminophen-induced liver injury in people (Harrill et al. 2009).
The JAX 36-strain MPP panel illustrated that genetic diversity among those mouse strains is comparable to the genetic diversity among humans (Harrill et al. 2009). With this in mind, the authors used the panel to model the phenotypic variation within the human population. Their results were not only practical but unexpected: the top acetaminophen toxicity modulating genes revealed by the MPP strains are related to the immune response, not to acetaminophen metabolism and detoxification (2009).
As the authors state, "The experimental approach we describe here, using acetaminophen as a model compound, bypasses the limitations of human-only pharmacogenetics studies by showing that a population of mouse strains can be used to predict genetic biomarkers of toxicity sensitivity" (Harrill et al. 2009).
The use of mouse panels offers researchers a unique tool for investigating drug toxicity but at a much lower cost and faster timeframe than human association studies. With this in mind, several genetically diverse mouse panels are available and others are being developed at JAX.
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If the "mouse panel-to-human" translational approach can be more widely applied, drug companies might be able to avoid late-stage setbacks and product recalls. Initial studies in mouse panels would greatly accelerate the identification of biomarkers and the development of tools for screening at-risk individuals before they are prescribed potentially toxic drugs.
"Just look at the drug industry's own numbers on how much it costs to develop a drug," remarks Dr. 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" (The Jackson Laboratory 2009).
As another of the study's co-authors, Paul Watkins, M.D., distinguished professor of medicine at the University of North Carolina, states, "...while drugs currently on the market are not entirely safe, they are harmless in 99.9% 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" (The Jackson Laboratory 2009).
The Jackson Laboratory can conduct drug efficacy testing studies on your compound utilizing the mouse panel approach. To inquire about these services and discuss the development of a study to meet your specific needs, please contact JAX® Services at 1-800-422-6423 or 1-207-288-5845.
References
Harrill AH, et al. 2009. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res, May 5 [Epub ahead of print].
