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. According to the Journal of Clinical Investigation study, treatment with one of these compounds produced a highly significant reduction in glycolipid levels in kidneys of male mice with Fabry disease. Equally important, the mice did not lose weight or develop toxic side effects from therapeutic levels of the inhibiting compound. We hope to show efficacy with oral intake, so the drug will not need to be given intravenously.