Genaissance Pharmaceuticals reports link between gene variants and drug response

Opening the door to personalized pharmaceuticals

Researchers at Genaissance Pharmaceuticals Inc. (New Haven, CT) and the University of Cincinnati College of Medicine have demonstrated, for the first time, that a response to a drug can be predicted from an individual's own DNA using genomic markers called haplotypes. The findings were reported in today's issue of the Proceedings of the National Academy of Sciences (see reference below).

The study involved 121 asthmatic volunteers who came to a clinic seeking relief from their symptoms. Lung function was measured before and after treatment with albuterol, a drug commonly used by physicians to achieve rapid improvement in lung function. The individual responses to albuterol were correlated to the sequence variations found in the gene encoding the (beta)2-adrenergic receptor, the target of albuterol. The receptor gene was found to have 13 different positions of sequence variation, or SNPs (single nucleotide polymorphisms). Theoretically, these 13 SNPs could be arranged into 213, or 8,192 possible haplotype (HAP Marker) combinations. However, Genaissance discovered that only 12 unique HAP Markers occur in nature and that only four were found in the majority of the patients.

"We found clear correlations between specific HAP Markers and clinical response to albuterol," said Stephen Liggett, the princiapl investigator for this study. "The drug response predictions could not have been made by using only the individual SNPs." Liggett is professor of medicine and molecular genetics at the University of Cincinnati College of Medicine, and executive medical advisor to Genaissance. "In addition, this technology allowed us to obtain very strong results from a modest number of patients."

The study is seen as a proof of concept for the Genaissance HAP technology, which, if commercialized, will herald an era where individual patients' DNA is used to guide the delivery of better, more personalized drugs. Genaissance has another clinical trial planned for asthma, and is looking ahead to other therapeutic areas such as cardiovascular disease, diabetes and schizophrenia.

Genaissance's approach organizes multiple positions of gene variation, SNPs, into haplotypes, or HAP markers, and correlates this information with clinical outcomes. HAP markers, analogous to genomic "barcodes," represent the distinct patterns of genomic variability that have accumulated over time in the human population. In many cases, this variation can explain why some people experience a better response to medication than others do. Conversely, it can also help explain why certain people develop side effects where others do not.

Seventeen million Americans are estimated to suffer from asthma, 4.8 million of whom are children under the age of 18. Approximately 5,000 people with asthma die each year. The healthcare costs associated with the disease are estimated to be six billion dollars per year.

Reference

Drysdale, C.M., McGraw, D., Stack, C.B., Stephens, J.C., Judson, R.S., Nandabalan, K., Arnold, K., Ruano, G., Liggett, S.B., Complex Promoter and Coding Region B(beta)2-adrenergic Receptor Haplotypes Alter Receptor Expression and Predict In Vivo Responsiveness. Proceedings of the National Academy of Sciences, 2000, 97: 10483-10488.

For more information: Paul Oestreicher, Genaissance Pharmaceuticals Inc., Five Science Park, New Haven, CT 06511. Tel: 203-773-1450. Fax: 203-562-9377.

Edited by Angelo DePalma
Managing Editor, Drug Discovery Online