Subcutaneous Replacement Enzymes for Fabry Disease

PROJECT SUMMARY Lysosomal storage diseasesLSDsare a large group of disorders that are caused by the absence offunctional enzymes used for the degradation of substances within lysosomesFabry disease is thesecond most prevalent LSD in the United States and worldwideIt is characterized by the absence offunctionalgalactosidase AGLAenzymes that breaks down globotriaosylceramideGLsubstratecausing the latter to accumulateIn addition to causing debilitating painGLaccumulation isparticularly damaging to the kidneys and heart requiring the need for cardiac proceduresdialysisand kidney transplantsCurrentlytreatment for Fabry disease in the United States consists of GLAenzyme replacement infusionsAlthough these biweekly infusions are clinically effective inarresting renal and cardiac organ damageintravenous treatments are inconvenientresource intensivetime consumingand expensiveFurthermorecurrent treatments bearpharmacological drawbacks such as short enzyme plasma half livesmin tohandinfusion related reactionsfeverchillsvomitinghypotensionparesthesiaassociated wit the administration of large single dosesUnfortunatelythe development of enzyme replacement therapiesERTsfor Fabry has remained stagnant for the pastdecadeand current efforts are focused on biosimilars that lack additional clinical or quality oflife benefitsThe aim of this research proposal is to optimize the formulation of a prototype subcutaneous ERTthat can be easily self administered in multiple discrete dosesThe prototype formulation to beoptimized consists of GLA enzymesa delivery vehiclehyaluronidaseand stability excipientsThe efforts in this project will set the groundwork to translate our subcutaneous approach into aclinically relevant product to complement or replace current intravenous treatmentsThis proposedstudy will focus onAimdeveloping highly concentrated subcutaneous GLA formulations anddetermining their stabilityandAimassessing the pharmacokinetic and biodistributionproperties of subcutaneous GLA formulations against a standard intravenous dose in a rat model