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Therapy Works for an 'Untreatable' Disease

Genetic engineering replaces missing enzyme

THURSDAY, July 5, 2001 (HealthDayNews) -- A genetically engineered therapy is working against a previously untreatable rare and fatal disease and may help people with similar inherited disorders, researchers report.

The treatment puts back an enzyme whose absence causes Fabry's disease, in which the relentless accumulation of molecules called sphingolipids in the blood vessels, heart, kidneys, eyes and other body parts causes progressive organ failure and early death. Sphingolipids are major components of cell membranes, particularly in the brain.

Daily injections of a laboratory-made version of the enzyme has produced definite results in 58 patients, report researchers headed by Dr. Robert J. Desnick, professor and chairman of the department of human genetics at Mount Sinai Medical Center in New York City.

"It's really exciting that we now have a specific treatment," says Desnick, whose findings are reported today in the New England Journal of Medicine.

Fabry's disease belongs to a family of inherited conditions called lysosomal storage diseases. People with the diseases lack an enzyme that stimulates cells to discard accumulating substances. Fabry's is the second such condition to be treated by enzyme replacement. The first was Gaucher's disease, which involves abnormal metabolism of a different sphingolipid.

"The proof of concept was in Gaucher's disease," Desnick says. "Until then, no one dreamed that you could treat a progressive lipid storage disease and actually reverse the process. The most that was hoped for was stabilization. It's quite dramatic that the treatment reverses the process."

A note of caution is raised by Dr. William A. Gahl, head of the section of human biochemical genetics at the National Institute of Child Health and Human Development and author of author of an accompanying journal editorial.

While Desnick's study shows that the underlying process of lipid accumulation has been stopped, Gahl says evidence that the physical deterioration of the patients has been slowed or stopped still are needed.

"These clinical parameters have to be proven by future studies. We're pretty far along but not all the way there yet," Gahl says.

That proof seems to be coming, says Desnick. "We're seeing patient improvement in terms of pain, sweating and general well-being. We are seeing clinical improvement in the patients," he says.

"We are reversing the pathology of the disease. If you reverse the pathology, you are bound to see clinical improvement," Desnick says.

Several medical centers are working on similar treatments for other lysosomal disorders, such as Pompe's disease and Niemann-Pick disease, Desnick says. "They are amenable to enzyme replacement treatment. We are quite excited about the prospects," he says.

But both Gahl and Desnick say enzyme replacement will not work where there is early nerve damage because the enzyme will not cross the blood-brain barrier. Gahl says, "You have to be selective. There are a whole slew of storage diseases that have neurological involvement."

These diseases are rare. For example, Fabry's disease occurs in 1 of every 40,000 to 50,000 births, meaning it affects perhaps 4,000 people in the United States. However, Desnick says, "Like other diseases for which a treatment is found, it is not uncommon for more cases to surface. We hope that undetected cases are diagnosed and come to treatment."

What To Do: Information about lysosomal storage diseases and experimental treatments are available at the Web sites of Niemann-Pick Disease and Pompe's Disease. A rundown on Fabry's disease is available from the National Institute of Neurological Disorders and Stroke.

SOURCES: Interviews with Robert J. Desnick, M.D., Ph.D., professor and chairman, Department of Human Genetics, Mount Sinai Medical Center, New York City; William A. Gahl, M.D., Ph.D., head, Section of Human Biochemical Genetics, National Institute of Child Health and Human Development; July 5, 2001, New England Journal of Medicine
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