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Chemical Extracted from Soy Beans Inhibits Disease Process Known as Amyloidogenesis

LA JOLLA, CA, October 4, 2005—Scientists at The Scripps Research Institute have discovered that a compound extracted from soy beans is a natural and potent inhibitor of a pathological process involved in a number of "amyloid" diseases, including a cluster of ailments called the familial amyloidoses.

Genistein, the soy extract, inhibits amyloidogenesis—the formation of fibril plaques that deposit in internal organs and interfere with their function. In clinically important familial amyloid diseases, these plaques are formed by the misfolding of the human protein transthyretin (TTR).

Misfolding of TTR is the cause of familial neuropathies and cardiomyopathies, and the Scripps Research team found that genistein could prevent it—at least in the test tube. The soy compound stabilizes TTR and prevents it from misfolding. This discovery, which is described in a paper to be published in an upcoming issue of the journal Proceedings of the National Academy of Sciences, suggests that genistein or a compound like it might someday be used to treat individuals suffering from familial amyloidoses.

The research was conducted in vitro, cautions the lead author of the report, Jeffery W. Kelly, Ph.D. More extensive in vivo preclinical studies and actual clinical studies would have to be conducted before the safety and potential of genistein to treat these diseases are known.

Kelly is the Lita Annenberg Hazen Professor of Chemistry, a member of The Skaggs Institute for Chemical Biology, and vice president of academic affairs at Scripps Research. He conducted the research with Scripps Research Institute postdoctoral fellow Nora S. Green, Ph.D., and Ted Foss, a Ph.D. candidate in the Scripps Research Kellogg School of Science and Technology.

Misfolding Causes Disease

Among the familial amyloid diseases known to medical science are a set called familial amyloid polyneuropathy (FAP), a collection of more than 80 rare amyloid diseases caused by the misfolding of transthyretin (TTR) mutants, which the liver secretes into the bloodstream to carry thyroid hormone and vitamin A.

Normally, TTR circulates in the blood as an active "tetramer" made up of four separate copies, or protein subunits, that bind to each other. These tetramers are usually composed of identical protein subunits.

Humans have two different genes that encode TTR subunits. Often in familial amyloid polyneuropathy, one of the genes has a heritable defect, and this causes hybrid tetramers to form that are composed of mutant and normal subunits. The inclusion of mutated subunits makes the tetramer less stable and causes the subunits to more easily dissociate. Once the subunits are free, they misfold and reassemble into hair-like amyloid fibrils.

These fibrils cause the disease FAP by building up around peripheral nerves, disrupting their function and leading to numbness, muscle weakness, and—in advanced cases—failure of the autonomic nervous system including the gastrointestinal tract. The current treatment for FAP is a liver transplant, which effectively replaces the mutant gene with a normal copy.

An analogous disease called familial amyloid cardiomyopathy (FAC) results from fibril formation in the heart, which leads to cardiac dysfunction. About one million African-Americans carry the mutated gene that predisposes them to FAC. Another amyloid disease affecting the heart, Senile Systemic Amyloidosis (SSA), afflicts an estimated 10 to 15 percent of all Americans over the age of 80 and results from the deposition of the normal form of transthyretin.

Stabilization Through Binding

Previously, scientists have tried administering drugs that inhibit the growth of fibrils from the misfolded state. However, this approach often proved ineffective because fibril formation is strongly favored once initiated.

Kelly and his laboratory have taken a new approach to prevent amyloid formation and amyloid diseases in the last few years. Instead of preventing the misfolded protein subunits from conglomerating to form plaques, he is preventing them from becoming abnormal monomeric subunits in the first place by stabilizing the proteins and keeping them folded in their proper "native state", a form that cannot form amyloid.

Recently, Kelly and his colleagues discovered a mechanism by which certain small molecules could inhibit amyloid formation. The small molecules bind to the TTR protein and stabilize the tetramer, making it harder for the subunits to dissociate and thus preventing the disease-associated subunits from contributing to fibril formation.

"Small molecules can prevent misfolding of TTR by making the barrier for tetramer dissociation insurmountable," says Kelly. "Owing to a familial TTR mutated subunit that prevents the onset of TTR amyloidosis by a strictly analogous mechanism, there is good reason to be optimistic that the small molecule approach would be effective at preventing amyloid diseases in humans."

In the current study, Kelly and his colleagues show that genistein may be a molecule that will do this. Interestingly, genistein is being tested in humans as a potential treatment for breast, prostate, and

uterine cancers and nutritionists have promoted soy in the diet because of the lower incidence of cancer in countries with a diet rich in soy.

The article, "Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis" is authored by Nora S. Green, Ted Foss, and Jeffery W. Kelly and is scheduled to appear in the October 11, 2005 issue of the journal Proceedings of the National Academy of Sciences. See:

The research was funded in part by the National Institutes of Health, Scripps Research's Skaggs Institute for Chemical Biology, the Lita Annenberg Hazen Foundation, and through a David and Ursula Fairchild Graduate Student Fellowship.

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