Medical College researcher working to make genetic-based medicine a reality

Wauwatosa, Wis. - Personalized medicine is a concept that appears a long way from becoming reality, but people in the know believe so-called genetic-based medicine is closer than we think.

In genetic-based medicine, personal genetic profiles will be used to identify the patient's predisposition to various diseases, and to develop disease management programs tailored to individual genetic and environmental characteristics.

Cracking the human genome has made personalized medicine possible, and advances in computing might further accelerate the pace of discovery, but researchers like Dr. Michael Stephens, assistant professor of pediatrics for the Medical College of Wisconsin, ultimately will make it happen.

Stephens, who joined MCW in 2002, has received a five-year, $634,500 pharmacogenetics grant from the National Institute of General Medical Sciences to study personal drug therapy. He will apply the grant to identify common genetic variants of key transporters of a class of drugs known as thiopurines.

Thiopurines are used in the treatment of cancer, arthritis, inflammatory bowel disease, and immune suppression. In an attempt to improve individualized treatment strategies with thiopurines, Stephens will examine their impact on therapeutic response in patients with inflammatory bowel disease. This class of drugs does not represent a flawless treatment. The performance of thiopurines varies significantly, and they have a high rate of toxicity and treatment failure.

"One of the problems with the drug is there is a lot of variation between individuals and how they respond to the drug," Stephens explained.

Specific genes can impact patient risk for having a specific toxicity, such as suppression of bone marrow, but that only explains a minority of the problems. For some genes, researchers have to discover variations that exist and how they impact drug metabolism and the transport of drugs.

By understanding how genetic variation impacts the drug transporter function, the medical community may be able to improve, and personalize, treatment strategies that include thiopurines.

Stephens' projects will attempt to identify and predict who will have a good response to the drugs, which patients will have a bad response, who will likely have no response, and who will experience side effects.

Project timetable

Stephens, who earned his doctor of medicine degree from the University of South Dakota, believes five years is a realistic time frame for the project. It will focus on two genes, MRP4 and MRP5, which serve as code for transporters in white blood cells.

In the beginning, the research will be based in the lab and use existing DNA samples, which will allow people on Stephens' research team to discover variants in specific genes. They will study the impact on cells that can be grown in a Petri dish.

Then, clinical trials will be conducted, following patients that receive thiopurnes, to validate those responses so the team can better predict "the right drug for people in the right dose," Stephens said.

In the clinical trials, researchers are likely to study patients who receive this drug for inflammatory bowel disease by measuring the level of the drug inside cells to determine how transporters are working.

"If problems cause transporters to work too slow or too well, that could be a predictor of toxicity or treatment failure," he said.

Collaboration call

As part of the pilot studies, Stephens plans to collaborate with other MCW researchers in the Departments of Pediatrics and Biostatistics, and with researchers at the Inflammatory Bowel Disease Center at Children's Hospital of Wisconsin. The grant sets up a collaborative effort not only in Wisconsin but a national collaboration involving multi-center analysis.

The Medical College of Wisconsin, which is southeastern Wisconsin's largest academic research center, is becoming known for its collaborative study, in part because agencies that distribute federal grants are basing their granting decisions on multi-institutional cooperation.

Earlier this year, in a study of genetically altered hemophilia mice, researchers at MCW and the Blood Center of Wisconsin announced they had discovered a possible genetic cure for hemophilia A patients, particularly those who don't respond to conventional blood transfusions.

Most of Stephens' work will be done in MCW's new facility with Children's Hospital. Stephens' lab will move into that facility, which is being designed to foster collaboration between departments.

In the new facility, Stephens' lab will be adjacent to MCW's Institute for Individualized Medicine, where researchers already collaborate on matters like how genes impact risk for heart disease and other conditions.

"The long-term goal is to conduct genetic testing and tailor doses based on your genes, on things that are unique to you," Stephens said.

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