FABRY DISEASE 025

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alpha-galactosidase A (GAL) is a lysosomal hydrolase enzyme responsible for the metabolism of globotriaosylceramide (GL-3), the enzyme's major glycosphingolipid substrate. In Fabry disease, an inherited deficiency of GAL leads to widespread deposition of GL-3, and to a lesser extent other Alpha -galactoside-containing glycolipids, in the heart, kidney, liver, skin, and intestines. The major clinical signs and symptoms of Fabry disease include skin lesions, benign corneal and lenticular opacities, excruciating acral pain, paresthesias, autonomic dysfunction, cardiac disease, and renal failure. Progressive glycolipid deposition in the microvasculature leads to failure of target organs resulting in death in the third to fifth decades of life. Because the X-chromosome carries the GAL gene, most affected patients are hemizygous males, although some heterozygous females can also be affected due to lyonization (random inactivation of one X-chromosome). The common element in the manifestations of Fabry disease is severe endothelial dysfunction affecting the structure, vasoreactivity and integrity of blood vessels. Ultimately, failure of endothelial vascular beds results in the myriad pathophysiologic events leading to central, peripheral and autonomic nervous system disease, cardiac disease and renal disease. Recently, enzyme replacement therapy for Fabry disease has been approved to market in several global markets including the European Union, Australia, and the United States (US). Genzyme Corporation has manufactured a recombinant form of human Alpha-galactosidase A (r-hGAL; Fabrazyme) to provide replacement enzyme to patients with Fabry disease. A Phase 1/2 single center, open label, dose finding, safety and pharmacokinetic study has been completed. This study provided evidence of pharmacodynamic clearance of stored glycosphingolipid from target tissues, suggesting physiologic improvement and potential for clinical benefit. A multi-national, randomized, double blind placebo controlled pivotal Phase 3 study has also been completed. The most frequent adverse events compared to placebo were infusion related (rigors and fever). In addition, laboratory studies including clinical chemistry, hematology, and urinalysis did not show that treatment with Fabrazyme had any direct toxic effects. Both trials demonstrated pharmacodynamic reduction to normal or near-normal levels of stored glycosphingolipid from vascular endothelial beds as surrogate endpoints likely to predict clinical benefit in Fabry patients. Detailed information regarding the non-clinical and clinical safety and efficacy of Fabrazyme is provided in the Investigator Brochure and/ or product labeling. This open-label trial is designed to demonstrate and confirm the safety and effectiveness of Fabrazyme in patients with Fabry dis