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. 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 result in the myriad pathophysiologic events leading to central, peripheral and autonomic nervous system disease, cardiac and renal disease. Genzyme Corporation has manufactured a recombinant form of human a-galactosidase A (r-ha-GAL; Fabrazyme) to provide replacement enzyme to patients with Fabry disease. A Phase 1-2 single center, open label, dose finding, safety and pharmacokinetic studies have 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 for those patients who received Fabrazyme compared to placebo were infusion-associated reactions including rigors and fever. In addition, laboratory studies including clinical chemistry, hematology, and urinalysis did not show that treatment with Fabrazyme had any toxic effects. Both trials have demonstrated pharmacodynamic reduction to normal or near-normal levels of stored glycospingolipids from vascular endothelial beds as surrogate endpoints likely to predict clinical benefit in Fabry patients.
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