Gene Expression in Drug-inflammation Models as Predictive of Idiosyncratic ADRs
Patricia E. Ganey, Ph.D., Principal Investigator, Michigan State University
Liver damage is a frequent and serious side effect of many candidate and even approved drugs. A team led by Patricia Ganey of Michigan State University will develop a rodent model system for testing which molecules might hurt the liver. The researchers will inject rats with both a dose of lipopolysaccharide, a molecule that by itself causes mild inflammation but no liver damage, and various drugs, some of which cause liver injury in certain patients. The researchers will look at gene activity in livers from treated rats and attempt to discover gene expression patterns that predict liver toxicity.
Proteome Mining as a Predictive Tool of Drug Toxicity
Timothy A. Haystead, Ph.D., Principal Investigator, Duke University
A team led by Timothy Haystead of Duke University will use innovative technology and a systematic approach to discover the underlying reason for many side effects: interactions between drug candidates and unintended proteins. Haystead’s group will use a technique they call proteome mining to detect these interactions. The researchers already have promising results in finding accidental associations with enzymes that use purines, the most common kind of human enzymes and the targets of many drugs. The group will test for such side-effect interactions in four different animal models.
Zebrafish Assays Predictive for Drug-Induced Cardiac Repolarization Toxicity
Calum A. Macrae, M.D., Ph.D., Principal Investigator, Massachusetts General Hospital
Some drugs accidentally disrupt the rhythms of electrical conduction in heart cells, which can cause life-threatening heartbeat irregularities. At this point, there is no good way to predict during drug development what molecules may have this side effect. Calum Macrae of Massachusetts General Hospital and his coworkers are developing a way of testing for possible cardiac side effects using larval zebrafish. They have already shown that drug-induced heart problems that occur in humans can be reproduced in the fish. The researchers hope to identify features that make drugs either toxic or safe for hearts.
Metabolomics: Markers of Drug-Induced Liver Injury
Susan J. Sumner, Ph.D., Principal Investigator, Research Triangle Institute
Susan Sumner of the Research Triangle Institute and her colleagues will also focus on drugs that cause liver injury. They plan to search for molecules—or metabolites—excreted in urine that can be used as early markers for liver damage. They hope to match specific markers with specific kinds of liver injury. Their approach of looking at a wide range of metabolites is also known as metabolomics.
Human Stem Cells for Toxicity Screening
Timothy R. Zacharewski, Ph.D., Principal Investigator, Michigan State University
Timothy Zacharewski of Michigan State University and his coworkers will attempt to develop human stem cells for the analysis of drug toxicity. In particular, they will test stem cells that have been developed into mimics of liver and kidney cells. The researchers’ goal is to produce a high-throughput screen for assessing the possible toxicity of molecules early in the drug development pipeline. They will also test how gene activity in human and rodent cells responds to different molecules and then attempt to pinpoint particular changes that could predict whether a wide range of drug candidates might be toxic or safe.
