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Potential New Treatment for Gaucher Disease Developed by Scientists at The Scripps Research Institute

La Jolla, CA. November 4, 2002 - A group of scientists at The Scripps Research Institute (TSRI) have developed a compound that could potentially be used as a new treatment for Gaucher disease, the most common genetic disorder affecting Jewish people of Eastern European ancestry. Although not tested in humans, the compound has shown great promise in human cell lines cultured from patients who suffer from the disease.

Patients with Gaucher disease may bruise easily due to low blood platelets, and they may have enlargement of the liver and spleen. Sometimes they experience fatigue due to anemia. The disease also causes cells in the bone marrow to become engorged with a fatty storage material, which may lead to bone lesions, weakening the skeleton, and sometimes resulting in painful fractures. In some instances, the disease also impairs the function of the lungs.

In an article that will be published in an upcoming issue of the journal Proceedings of the National Academy of Sciences, the TSRI group describes using small molecules to partially correct the genetic defect that underlies most cases of Gaucher disease. The defect prevents a crucial metabolic enzyme from reaching the location in the cell where it normally functions, but the small molecules act as "chaperones," guiding the mutant enzyme to the right location and allowing it to survive and function.

"This is an entirely new approach to the disease," says TSRI Professor Ernest Beutler, M.D., who is one of the authors of the study and one of the world's leading experts on Gaucher disease and similar metabolic disorders. Beutler's laboratory was the first to clone the gene responsible for Gaucher disease in the mid-1980s.

"And it may be less costly and more convenient than the current treatment," adds Jeffery W. Kelly, who is the Lita Annenberg Hazen Professor of Chemistry and vice president of academic affairs at TSRI. Kelly led the research effort along with the study's first author, Anu Sawkar, a Ph.D. student in TSRI's Kellogg School of Science and Technology.

A New Approach to an Old Disease

Gaucher disease, which is named after the French dermatologist Phillipe Gaucher, who first described the condition in 1882, is a genetic disease caused by heritable defects of an important metabolic enzyme called lysosomal β-glucosidase. People with Gaucher disease have one or more defects in their β-glucosidase genes, and these defects corrupt their β- glucosidase enzyme. Some of these corrupted enzymes are apparently unstable because they cannot fold properly into their correct three-dimensional structure.

Normally β-glucosidase resides and functions in macrophage lysosomes - the sac-like organelles that recycle macromolecules inside cells - where it breaks down fatty substances known as glucosylceramides. But the corrupted, mutant enzyme may fail to reach the lysosome, and as a result, the fatty glucosylceramides accumulate there. The macrophages become engorged with glucosylceramide-swollen lysosomes, which causes problems in the spleen, liver, lungs, bone marrow - and, in rare cases, the brain.

There are dozens of different mutations that can cause Gaucher disease, and the prevalence of the disease varies widely in different ethnic populations. Most at risk for the disease are individuals of Eastern European Jewish ancestry (the so-called Ashkenazi Jews), among whom about 1 in 14 carry one copy of one of the mutations of β-glucosidase. As a result, the prevalence of Gaucher disease among Ashkenazi Jews has been estimated to be about 1 in 800. In the general population, about 1 in every 40,000 to 100,000 people have Gaucher disease.

The current approaches to treating Gaucher disease involve replacing the deficient enzyme, thereby breaking down the accumulated glucosylceramide and preventing it from accumulating. Enzyme replacement therapy is a highly effective way to restore people to good health, but it has a couple of serious drawbacks.

The enzyme has to be infused intravenously or through a surgically implanted catheter - usually in a doctor's office - a process that takes several hours and must be repeated every one or two weeks. Enzyme replacement therapy is also extremely expensive, costing between $100,000 and $750,000 per year per patient. And the therapy is not effective at treating neurological complications of Gaucher disease.

Now Kelly, Beutler, and their colleagues at TSRI report positive results on a radically different approach that may address some of the problems with enzyme replacement therapy. Rather than replacing the mutant enzyme, says Kelly, "We use a small molecule to partially correct [its] imperfections."

Their small molecule "chaperone" stabilizes the mutant β-glucosidase enzyme, helping it to fold properly and find its way to the lysosome, where it can degrade the fatty substance.

The chaperone targets the most common Gaucher mutation, which is referred to as "1226G" or "N370S." Virtually every Jewish patient with Gaucher disease has this β-glucosidase mutation.

A therapy based on these chaperones has the potential to be much more convenient and less costly than enzyme replacement, because small molecules could be taken orally and would be cheaper to mass-produce than whole enzymes. In addition, small molecules can be found that cross the blood-brain barrier, and perhaps address the neurological complications of Gaucher disease, if they are caused by mutants that respond to chaperone therapy.

The article, "Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease" was authored by Anu R. Sawkar, Wei-Chieh Cheng, Ernest Beutler, Chi-Huey Wong, William E. Balch, and Jeffrey W. Kelly, and appears in the online edition of the journal Proceedings of the National Academy of Sciences the week of November 4, 2002. The article will appear in print later this year.

This work was supported by The Skaggs Institute for Research, the Lita Annenberg Hazen Foundation, the Stein Endowment Fund, and a National Science Foundation Predoctoral Fellowship.

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