News Release

Millennium Clones Diet-Induced Obesity Gene

Peer-Reviewed Publication

Noonan/Russo Communications

CAMBRIDGE, Mass. March 11, 1999 -- Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM) has cloned the first gene that can suppress diet-induced obesity in mice. The gene may have strong implications in developing therapies to intervene in human obesity, the authors note in their report, which appears in the March 11, 1999 issue of Nature.

The scientists found that while the gene, called mahogany (mg), produces a protein (MG) in many tissues of the body, its activity in a specific region of the brain's hypothalamus is particularly interesting because of that region's role in body weight regulation.

"The cloning of the mahogany gene and the identification of its protein product are major first steps in achieving a better understanding of their roles in controlling weight based on the amount of fat in a diet," said Karen Moore, Ph.D., director of genetic systems at Millennium. Because of the great similarity between mouse and human metabolism, the scientists expect to find that the gene plays a similar role in people.

Mice with a mutation in their mg gene maintain a healthy weight whether they eat a high fat (42 percent fat) or low fat (9 percent fat) diet with the same amount of calories. In contrast, mice with a normal mg gene gain excess weight on the high fat diet. Such diet-induced obesity differs from forms of genetically-induced obesity in which weight gain occurs even when mice are fed a normal diet. Genetically induced obesity in mice has been linked to mutations in the obese (ob), diabetes (db), tubby (tub), fat (fat) and agouti-yellow (Ay) genes. Mice with a mutation in their mg gene can suppress the genetic induced obesity of agouti-yellow mice but not that of ob, db, tub and fat mice.

The structure of the large MG protein is complex and can occur in two major forms. One form spans the cell wall leaving multiple sections of the protein to project outside the cell, which may function as receptors to which small proteins called peptides bind, causing a cascade of cellular events. A receptor, the MG protein lends itself to serve as a target for drug development, noted Dr. Moore. Also, a small portion of the protein's end sticks into the cell's interior, which may act to signal internal cell activity upon peptide binding. The protein also occurs in a secreted form. Dr. Moore and her team are now exploring possible modes of action for the protein, using clues from its structure and from cell biology.

Genetic and biological evidence indicates that the MG molecule might function to gather, concentrate and present antagonists that block the function of certain weight-regulating melanocortin receptors, thereby enhancing the receptors' signaling, explains Dr. Moore. In agouti-yellow mice, which were used in the Millennium study, the agouti gene overexpresses its protein product, which is such an antagonist, thereby blocking the melanocortin receptor, and the mice can become obese. However, the mutant mg gene suppresses this weight gain, keeping agouti-yellow mice at normal weight, perhaps by preventing effective antagonism by the agouti gene product.

Alternatively, the scientists suggest, the MG protein itself may be a signaling receptor, but they are unsure about how MG may function in this mode.

"Because the desired affect is obtained when the mahogany gene is defective, we are optimistic about using the protein for obesity drug development. In developing a drug, it is always easier to decrease gene function rather than to try to increase it," says Dr. Moore.

The strong similarity between the mouse and human genomes should enable the use of the MG protein as a target for screens that test the function and effectiveness of different compounds for possible human obesity therapies.

"The targetability of the mahogany protein offers us an excellent opportunity to pursue the development of a small molecule that could attach to a receptor and affect the protein's function. If successful, the small molecule could become the basis of a drug for obesity," said Robert Tepper, M.D., chief scientific officer, pharmaceutical division of Millennium.

Human obesity, being more than 20 percent over an ideal weight, greatly increases the risk for the development of diabetes, heart disease, high blood pressure and stroke. In the United States, more than one third of adults--50 million people--are obese, reports the National Institute of Diabetes and Digestive and Kidney Diseases, part of the U.S. National Institutes of Health.

To locate the mg gene, Dr. Moore and her colleagues used a technique called positional cloning, in which scientists work backwards from examining a specific disease trait and then search for the responsible genetic cause. Their study is the first report of the use of this technique to identify a suppressor gene in a mouse.

A separate study in the same issue of Nature by Gregory S. Barsh, M.D., of Stanford University School of Medicine and colleagues also reports the cloning of the mg gene and that it encodes a large protein that spans the cell membrane. Both the Millennium and the Stanford research teams note the similarity of the mg gene and a human gene called attractin, a recently identified molecule that circulates in the body and is implicated in the interactions of immune system cells.

Dr. Moore's co-authors from Millennium include Deborah L. Nagle, Ph.D., Sonja H. McGrail, James Vitale, Elizabeth A. Woolf, Barry J. Dussault, Jr., Lisa DiRocco, Lisa Holmgren, Jill Montagno, Dennis Huszar, Ph.D., Victoria Fairchild-Huntress, M.S., Pei Ge, and John Keilty. Other co-authors include Peer Bork, Ph.D., of the European Molecular Biology Laboratories in Heildelberg, Germany and the Max-Delbruck-Center for Molecular Medicine in Berlin-Buch; Chris Ebeling, Linda Baldini, Julie Gilchrist and George A. Carlson, Ph.D., of the McLaughline Research Institute for Biomedical Sciences in Great Falls, MT; and Paul Burn, Ph.D., of the Department of Metabolic Diseases at Hoffman-La Roche in Nutley, N.J. Hoffman-La Roche supported the research.

Millennium, a leading drug discovery and development company, employs large-scale genetics, genomics, high throughput screening and informatics in an integrated science and technology platform. This innovative drug discovery platform is applied across the entire healthcare sector, from gene identification through patient management, to accelerate and transform the discovery and development of proprietary therapeutic and diagnostic products and services. Headquartered in Cambridge, Massachusetts, Millennium and its affiliates currently employ more than 700 people.

This press release contains forward-looking statements that involve a number of risks and uncertainties. Among the factors that could cause actual results to differ materially from those indicated in such forward looking statements include uncertainties relating to gene identification, drug discovery and clinical development processes; changes in relationships with strategic partners and dependence upon strategic partners for the performance of critical activities under collaborative agreements; the impact of competitive products and technological changes; uncertainties relating to patent protection and regulatory approval; and uncertainties relating to the ability of Millennium and its affiliates to obtain the substantial additional funds required for progress in drug discovery and development. The factors that could affect the performance of Millennium are more fully described in filings by Millennium with the Securities and Exchange Commission including but not limited to the factors set forth under the heading ``Business - Factors That May Affect Results'' in the Annual Report on Form 10-K of Millennium for the year ended December 31, 1997 as filed on March 31, 1998.

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Editors Note: This press release, accompanying graphics and other supporting materials are available at: http://www.eurekalert.org & http://www.noonanrusso.com/www/mlnm/entry.ihtml



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