A New Treatment for Gaucher? Compound Intrigues

By Lea Winerman

Published August 15, 2003, issue of August 15, 2003.
  • Print
  • Share Share

Researchers have developed a chemical compound that could lead to a new treatment for Gaucher disease, the most common genetic disease among Ashkenazi Jews, which causes problems including anemia, poor blood clotting, an enlarged liver and spleen, bone damage and, in the most serious cases, neurological problems.

The newly discovered compound is made up of small molecules that stabilize and correct the defective enzyme responsible for these symptoms. Its development, which was reported last November in the Proceedings of the National Academy of Sciences, may lead to a new therapy that is both less expensive and more convenient than the current Gaucher treatment. The current treatment, enzyme replacement therapy, can cost $100,000 to $750,000 per year and must be administered intravenously.

The new compound has not yet been tested in humans, however, and is likely years away from becoming a viable treatment option. Still, said Ernest Beutler, a professor at the Scripps Research Institute and a co-author of the study, “the fact that there is a new approach to treating this and other diseases is encouraging. Ten years ago no one was even thinking of this.”

Gaucher disease affects approximately one in 450 Ashkenazi Jews. Like Tay-Sachs disease and several other inherited disorders, it is a lysosomal storage disease. Lysosomes are the body’s recycling centers, present in every cell. Inside them, enzymes break down complex cell parts such as proteins and lipids into simpler pieces that the cell can reuse. When a particular enzyme is not working correctly, the material that it is supposed to break down builds up inside the cell instead. Gaucher disease patients have genetic mutations that cause defects in an enzyme that is supposed to break down a fatty substance called glucosylceramide.

Enzyme replacement therapy, the gold standard Gaucher treatment right now, works by replacing the defective enzyme. It works well for many patients, but it is not without difficulties: Patients must receive injections of the replacement enzyme as often as several times per week, either intravenously or through a surgically implanted catheter. Enzyme replacement therapy also cannot help patients with neurological damage from the most severe type of Gaucher disease.

Another treatment for Gaucher disease is available to patients in Europe and Israel. Miglustat, which can be taken orally, reduces the amount of glucosylceramide that the body produces and so reduces the amount of it that can accumulate in cells. But this treatment also has problems: Glucosylceramide has necessary functions in the body, so getting rid of it can cause toxic effects. Miglustat is not available in the United States because it has not yet been approved by the Food and Drug Adminis-

tration, and in other countries it is only available to patients who cannot tolerate enzyme replacement therapy.

Unlike these options, the new treatment would work with the patients’ own enzymes to correct their deficiencies. In their study, the Scripps Research Institute researchers added the small molecules to cells taken from a Gaucher patient. The molecules acted as chemical “chaperones” to shepherd the defective enzymes through the cell to their target in the lysosome and to keep them from misfolding or going astray. The researchers found that adding these small molecules to the cells doubled the activity of the deficient enzyme.

The researchers’ approach is not unique. In the past several years, scientists have successfully applied similar strategies to cells from patients with Fabry disease, another lysosomal storage disorder. A treatment based on these small chaperone molecules could potentially be taken orally, making it more convenient than enzyme replacement therapy. It also has the potential, said Beutler, to treat neurological symptoms of Gaucher disease.

“I think this is a promising avenue to explore,” said Ari Zimran, director of the Gaucher clinic at Shaare Zedek Hospital in Jerusalem. Zimran also noted that another recent study described, for the first time, the structure of the defective enzyme that causes Gaucher disease. “If one combines the concept of the chaperone molecules with the new knowledge of the structure of the enzyme, it may lead to new therapeutic options,” he said.

Those treatments, however, may not come any time soon, he said. Because Gaucher patients are a relatively small population, it may be difficult to convince pharmaceutical companies to invest money in developing new treatments for the disease.

Beutler also said that a long road remains before any new treatment options become available. He and his colleagues are working now to refine and optimize the compound, and have not yet started to consider human trials. “It’s still quite a ways away,” he said.

Elaine Benton, for one, would appreciate the new treatment option. Benton, 40, was 5 years old when she was diagnosed with Gaucher disease, and she has experienced the gamut of Gaucher treatments. When she was a child, her doctors could do little to help her except try to ease the disease’s symptoms, which for her ranged from an enlarged liver and spleen to excruciatingly painful bone crises.

In 1991 she began to use the newly available enzyme replacement therapy. “There was quite a remarkable difference right from the beginning of the treatment,” Benton said. “It was marvelous.” Benton has now responded well to the therapy for 12 years.

A treatment that could be taken orally would be even better, she said. “I don’t think there’s any Gaucher patient who wouldn’t like that.”

Find us on Facebook!
  • "It’s the smell that hits me first — musty, almost sweet, emanating from the green felt that cradles each piece of silver cutlery in its own place." Only one week left to submit! Tell us the story of your family's Jewish heirloom.
  • Mazel tov to Chelsea Clinton and Marc Mezvinsky!
  • If it's true, it's pretty terrifying news.
  • “My mom went to cook at the White House and all I got was this tiny piece of leftover raspberry ganache."
  • Planning on catching "Fading Gigolo" this weekend? Read our review.
  • A new initiative will spend $300 million a year towards strengthening Israel's relationship with the Diaspora. http://jd.fo/q3Iaj Is this money spent wisely?
  • Lusia Horowitz left pre-state Israel to fight fascism in Spain — and wound up being captured by the Nazis and sent to die at Auschwitz. Share her remarkable story — told in her letters.
  • Vered Guttman doesn't usually get nervous about cooking for 20 people, even for Passover. But last night was a bit different. She was cooking for the Obamas at the White House Seder.
  • A grumpy Jewish grandfather is wary of his granddaughter's celebrating Easter with the in-laws. But the Seesaw says it might just make her appreciate Judaism more. What do you think?
  • “Twist and Shout.” “Under the Boardwalk.” “Brown-Eyed Girl.” What do these great songs have in common? A forgotten Jewish songwriter. We tracked him down.
  • What can we learn from tragedies like the rampage in suburban Kansas City? For one thing, we must keep our eyes on the real threats that we as Jews face.
  • When is a legume not necessarily a legume? Philologos has the answer.
  • "Sometime in my childhood, I realized that the Exodus wasn’t as remote or as faceless as I thought it was, because I knew a former slave. His name was Hersh Nemes, and he was my grandfather." Share this moving Passover essay!
  • Getting ready for Seder? Chag Sameach! http://jd.fo/q3LO2
  • from-cache

Would you like to receive updates about new stories?

We will not share your e-mail address or other personal information.

Already subscribed? Manage your subscription.