Researchers Show First Evidence Of Pharmacogenomic Differences In Patients' Responses To MS Drug

Their results show that IFN-beta-1a initiates different patterns of genetic expression in different MS patients, information that could lead to better, and potentially individualized, treatments.

Results of the study were presented Oct. 21 at the annual meeting of the American Neurological Association in San Francisco by Bianca Weinstock-Guttman, M.D., UB assistant professor of neurology and director of the Baird MS Center at The Jacobs Neurological Institute, the research arm of the UB Department of Neurology. The study also appeared in the September issue of The Journal of Immunology.

The work links gene microarray techniques with the science of pharmacogenomics and pharmacodynamics. Microarrays are tools for measuring the expression of large numbers of genes. Pharmacodynamics uses mathematical models to capture the details of how drugs affect the body's systems over time, starting with the moment of exposure to the drug.

Together, these techniques can be used to find how genes interact with each other and how a cell's regulatory networks control vast batteries of genes simultaneously. Murali Ramanathan, Ph.D., UB associate professor of pharmaceutical sciences, who performed the experimental assays, has broad experience in processing and analyzing this complex information.

"In a small group of patients, we found that the mRNA gene expression in response to IFN-beta-1a increased rapidly in some MS patients, and was low and late in other patients," said Weinstock-Guttman. "We were very surprised that some of the gene markers showed up as early as two hours after we administered the drug. Prior to this work, other investigators in the field often assumed a 12-hour or more response time was required. Our next step is to correlate this pattern with the patient's clinical response to the drug.

"This process may allow clinicians to learn the specific treatment 'signature' quickly and eventually to be able to modify treatment plans rationally," said Frederick Munschauer, M.D., professor and chair of the Department of Neurology in the UB School of Medicine and Biomedical Sciences and chief of The Jacobs Neurological Institute.

The effects of IFN-beta-1a at the genetic level are poorly understood, and the effectiveness, especially in MS patients, differs from person to person and is difficult to monitor. Magnetic resonance imaging (MRI) scans, considered the best way to monitor patients with MS currently, have shown complete suppression of new brain lesions in approximately 40 percent of IFN-beta-1a treated patients, while 20 percent show only 70 percent or less suppression, said Weinstock-Guttman.

In the current study, the UB researchers administered IFN-beta-1a to eight MS patients. They drew blood samples before giving the drug and at 1, 2, 4, 8, 24, 48, 120 and 168 hours after the first injection. Standard IFN-beta-1a treatment is a weekly intramuscular injection.

The immune cells in blood were separated and their gene-expression profile processed and amplified using cDNA microarrays. The data on specific genes of interest were validated using an additional technique called real-time reverse transcriptase polymerase chain reaction, or RT- PCR, which supported the primary array findings, said Weinstock-Guttman.

"IFN therapy in MS patients is associated with a complex gene-expression modulation. The pharmacodynamic profiles indicate that changes in the gene expression occur as early as 1-4 hours of injection and that these changes modulate the immune system.

"Our results support the premise that gene expression profiling using microarray techniques and studying the pharmacodynamics may lead to improved, possibly individualized, IFN-beta-1a regimens in MS patients. This work also emphasizes the value of interdepartmental collaboration in answering complex questions such as this."

Additional researchers on the study were: Kara Patrick and Joan Feichter from the Jacobs Neurological Institute; Darlene Badgett, research specialist, and graduate students Roseane Santos, Dennis Hall and Laura Hartrich from the Department of Pharmaceutical Sciences in the UB School of Pharmacy and Pharmaceutical Sciences, and Monika Baier, Ph.D., from the Department of Statistics at the Cooper Institute, Colden, CO.

The research was supported by a grant from the National Multiple Sclerosis Society.