The University Record, June 19, 2000

Experimental drug reverses effects of Fabry disease

By Sally Pobojewski
Health System Public Relations

These images are representative electron micrographs of kidney cells from U-M experimental and control mice. The image on the left shows cells from untreated mice with Fabry disease. The large dark objects are vesicles filled with glycolipids; the circular object on the right is the cell’s nucleus. Kidney cells on the right, from Fabry-diseased mice receiving the U-M inhibitor, contain small, lipid-rich vesicles consistent with the loss of glycolipid. Original magnification: x3,280. Photos courtesy James Shayman
A new experimental drug developed at the Medical School is the first treatment shown to reverse the effects in mice of a hereditary, incurable disorder called Fabry (Fah-BRAY) disease, which affects between 6,000 and 10,000 men in the United States.

Results of the study were published in the June 2000 issue of the Journal of Clinical Investigation in an article by James Shayman, professor of pharmacology and of internal medicine, and colleagues from the U-M and the National Institutes of Health.

Fabry disease is caused by a genetic mutation that prevents production of an enzyme called alpha-galactosidase A, which cells store in tiny globules called lysosomes. The cellular version of a garbage disposal, lysosomes are found in all cells that use enzymes to dissolve specific molecular bonds and digest waste products.

Without alpha-galactosidase A, lysosomes cannot break up one particular type of glycolipid, a long chain of fats and sugars found in cell membranes. As a result, these molecules accumulate within the kidneys, hearts and blood vessels of patients with Fabry disease. Death occurs in early adulthood from renal failure or cardiovascular complications.

For the past 10 years, U-M researchers have been developing and perfecting a family of glycolipid synthesis inhibitors for use in Fabry disease, according to Shayman. “Other researchers tried to replace the missing enzyme, but we concentrated on blocking glycolipid formation by inhibiting a key enzyme the cell needs to produce these molecules. We now have two compounds with high levels of inhibitory activity and no observed toxic side effects.”

According to the Journal of Clinical Investigation article, treatment with one of these compounds produced a highly significant reduction in glycolipid levels in kidneys of male mice with Fabry disease. When treated for eight weeks with twice-daily injections, glycolipid levels after treatment were lower than they were before treatment began—a result Shayman described as the most unexpected in the study. Equally important, the mice did not lose weight or develop toxic side effects from therapeutic levels of the inhibiting compound.

“Now that we know it works in mice, our next step is pre-clinical drug development,” Shayman says. “We hope to show efficacy with oral intake, so the drug will not need to be given intravenously. Then, we plan to apply for Investigational New Drug approval and orphan disease designation from the Food and Drug Administration prior to the initiation of clinical trials.”

Fabry disease is called an “orphan disease” because it is so rare. According to Shayman, however, six other lysosomal storage diseases are closely related to Fabry and should be treatable with the same approach. Together these seven diseases affect between 20,000 and 30,000 people in the United States. Although caused by different missing enzymes, all seven diseases are characterized by accumulations of similar types of glycolipids in different organs in the body. Since the U-M compound inhibits production of these glycolipids, Shayman plans to test its effectiveness in these related disorders, which include Gaucher disease, Tay-Sachs disease, Sandhoff disease and GM1 gangliosidosis.

“Currently only Gaucher disease has an approved therapy, which involves regular intravenous infusions of a genetically engineered form of the missing enzyme called recombinant beta-glucosidase,” Shayman says. “It costs more than $200,000 for one year’s treatment and currently is the most expensive drug on the market.”

The U-M has received several patents and filed additional patent applications related to glycolipid synthesis inhibitors. This study was supported by grants from the National Institutes of Health and the Veterans Administration.

Other scientists from the Medical School involved in the study include Akira Abe, research investigator; Susan Gregory, research assistant, Libsueh Lee, research associate; and Paul D. Killen, associate professor of pathology. Collaborators from the National Institutes of Health include research scientists Roscoe O. Brady and Ashok Kulkarni.